Experimental cancer genetics

The Experimental cancer genetics team aims to understand the fundamental genetic mechanisms by which cancers develop.

Their approach to use large-scale DNA sequencing to identify candidate cancer genes and to study these genes in model systems such as in mice and cells. Another aspect of their work is to perform genetic screens in models systems using tools such as CRISPR and transposons. A particular interest is synthetic lethality, essential genes and immune modulators.

[Anne Weston, Wellcome Images]

Background

The genetic basis of cancer

Cancer occurs when there is an accumulation of genetic damage that confers a selective advantage on a cell, allowing it to evade normal growth control processes. Uncontrolled growth and reproduction of these damaged cells ultimately results in tumour formation. While some of the key events at the molecular level that are involved in cancer formation are known, there is still much work to be done to identify other genetic changes important in cancer formation that could represent new diagnostic markers or targets for new anti-cancer medicines.

Selected publications

  • Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma.

    Aoude LG, Pritchard AL, Robles-Espinoza CD, Wadt K, Harland M, Choi J, Gartside M, Quesada V, Johansson P, Palmer JM, Ramsay AJ, Zhang X, Jones K, Symmons J, Holland EA, Schmid H, Bonazzi V, Woods S, Dutton-Regester K, Stark MS, Snowden H, van Doorn R, Montgomery GW, Martin NG, Keane TM, López-Otín C, Gerdes AM, Olsson H, Ingvar C, Borg A, Gruis NA, Trent JM, Jönsson G, Bishop DT, Mann GJ, Newton-Bishop JA, Brown KM, Adams DJ and Hayward NK

    Journal of the National Cancer Institute 2015;107;2

  • Telomere-Regulating Genes and the Telomere Interactome in Familial Cancers.

    Robles-Espinoza CD, Del Castillo Velasco-Herrera M, Hayward NK and Adams DJ

    Molecular cancer research : MCR 2015;13;2;211-222

  • Transposon mutagenesis identifies genes and evolutionary forces driving gastrointestinal tract tumor progression.

    Takeda H, Wei Z, Koso H, Rust AG, Yew CC, Mann MB, Ward JM, Adams DJ, Copeland NG and Jenkins NA

    Nature genetics 2015;47;2;142-50

  • The mutational landscapes of genetic and chemical models of Kras-driven lung cancer.

    Westcott PM, Halliwill KD, To MD, Rashid M, Rust AG, Keane TM, Delrosario R, Jen KY, Gurley KE, Kemp CJ, Fredlund E, Quigley DA, Adams DJ and Balmain A

    Nature 2015;517;7535;489-92

  • A high-throughput in vivo micronucleus assay for genome instability screening in mice.

    Balmus G, Karp NA, Ng BL, Jackson SP, Adams DJ and McIntyre RE

    Nature protocols 2015;10;1;205-15

  • BRAF/NRAS wild-type melanoma, NF1 status and sensitivity to trametinib.

    Ranzani M, Alifrangis C, Perna D, Dutton-Regester K, Pritchard A, Wong K, Rashid M, Robles-Espinoza CD, Hayward NK, McDermott U, Garnett M and Adams DJ

    Pigment cell & melanoma research 2015;28;1;117-9

  • Disruption of the potassium channel regulatory subunit KCNE2 causes iron-deficient anemia.

    Salsbury G, Cambridge EL, McIntyre Z, Arends MJ, Karp NA, Isherwood C, Shannon C, Hooks Y, Sanger Mouse Genetics Project, Ramirez-Solis R, Adams DJ, White JK and Speak AO

    Experimental hematology 2014;42;12;1053-8.e1

  • Mutation, clonal fitness and field change in epithelial carcinogenesis.

    Frede J, Adams DJ and Jones PH

    The Journal of pathology 2014;234;3;296-301

  • Cancer gene discovery goes mobile.

    van der Weyden L, Ranzani M and Adams DJ

    Nature genetics 2014;46;9;928-9

  • A strategy to identify dominant point mutant modifiers of a quantitative trait.

    Dove WF, Shedlovsky A, Clipson L, Amos-Landgraf JM, Halberg RB, Krentz KJ, Boehm FJ, Newton MA, Adams DJ and Keane TM

    G3 (Bethesda, Md.) 2014;4;6;1113-21

  • POT1 loss-of-function variants predispose to familial melanoma.

    Robles-Espinoza CD, Harland M, Ramsay AJ, Aoude LG, Quesada V, Ding Z, Pooley KA, Pritchard AL, Tiffen JC, Petljak M, Palmer JM, Symmons J, Johansson P, Stark MS, Gartside MG, Snowden H, Montgomery GW, Martin NG, Liu JZ, Choi J, Makowski M, Brown KM, Dunning AM, Keane TM, López-Otín C, Gruis NA, Hayward NK, Bishop DT, Newton-Bishop JA and Adams DJ

    Nature genetics 2014;46;5;478-81

  • Identification of FoxR2 as an oncogene in medulloblastoma.

    Koso H, Tsuhako A, Lyons E, Ward JM, Rust AG, Adams DJ, Jenkins NA, Copeland NG and Watanabe S

    Cancer research 2014;74;8;2351-61

  • Cross-species analysis of mouse and human cancer genomes.

    Robles-Espinoza CD and Adams DJ

    Cold Spring Harbor protocols 2014;2014;4;350-8

  • Insertional mutagenesis and deep profiling reveals gene hierarchies and a Myc/p53-dependent bottleneck in lymphomagenesis.

    Huser CA, Gilroy KL, de Ridder J, Kilbey A, Borland G, Mackay N, Jenkins A, Bell M, Herzyk P, van der Weyden L, Adams DJ, Rust AG, Cameron E and Neil JC

    PLoS genetics 2014;10;2;e1004167

  • Inactivating CUX1 mutations promote tumorigenesis.

    Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C, Alexandrov LB, Tiffen JC, Kober C, Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium, Green AR, Massie CE, Nangalia J, Lempidaki S, Döhner H, Döhner K, Bray SJ, McDermott U, Papaemmanuil E, Campbell PJ and Adams DJ

    Nature genetics 2014;46;1;33-8

  • Transposon mutagenesis identifies genes driving hepatocellular carcinoma in a chronic hepatitis B mouse model.

    Bard-Chapeau EA, Nguyen AT, Rust AG, Sayadi A, Lee P, Chua BQ, New LS, de Jong J, Ward JM, Chin CK, Chew V, Toh HC, Abastado JP, Benoukraf T, Soong R, Bard FA, Dupuy AJ, Johnson RL, Radda GK, Chan EC, Wessels LF, Adams DJ, Jenkins NA and Copeland NG

    Nature genetics 2014;46;1;24-32

  • Identification of structural variation in mouse genomes.

    Keane TM, Wong K, Adams DJ, Flint J, Reymond A and Yalcin B

    Frontiers in genetics 2014;5;192

  • Impact of temporal variation on design and analysis of mouse knockout phenotyping studies.

    Karp NA, Speak AO, White JK, Adams DJ, Hrabé de Angelis M, Hérault Y and Mott RF

    PloS one 2014;9;10;e111239

  • One patient, two lesions, two oncogenic drivers of gastric cancer.

    Alsinet C, Ranzani M and Adams DJ

    Genome biology 2014;15;8;444

  • Targeting of Slc25a21 is associated with orofacial defects and otitis media due to disrupted expression of a neighbouring gene.

    Maguire S, Estabel J, Ingham N, Pearson S, Ryder E, Carragher DM, Walker N, Sanger MGP Slc25a21 Project Team, Bussell J, Chan WI, Keane TM, Adams DJ, Scudamore CL, Lelliott CJ, Ramírez-Solis R, Karp NA, Steel KP, White JK and Gerdin AK

    PloS one 2014;9;3;e91807

  • Spindle assembly checkpoint of oocytes depends on a kinetochore structure determined by cohesin in meiosis I.

    Tachibana-Konwalski K, Godwin J, Borsos M, Rattani A, Adams DJ and Nasmyth K

    Current biology : CB 2013;23;24;2534-9

  • Sleeping Beauty mutagenesis in a mouse medulloblastoma model defines networks that discriminate between human molecular subgroups.

    Genovesi LA, Ng CG, Davis MJ, Remke M, Taylor MD, Adams DJ, Rust AG, Ward JM, Ban KH, Jenkins NA, Copeland NG and Wainwright BJ

    Proceedings of the National Academy of Sciences of the United States of America 2013;110;46;E4325-34

  • Cancer gene discovery: exploiting insertional mutagenesis.

    Ranzani M, Annunziato S, Adams DJ and Montini E

    Molecular cancer research : MCR 2013;11;10;1141-58

  • Cake: a bioinformatics pipeline for the integrated analysis of somatic variants in cancer genomes.

    Rashid M, Robles-Espinoza CD, Rust AG and Adams DJ

    Bioinformatics (Oxford, England) 2013;29;17;2208-10

  • Cooperativity and rapid evolution of cobound transcription factors in closely related mammals.

    Stefflova K, Thybert D, Wilson MD, Streeter I, Aleksic J, Karagianni P, Brazma A, Adams DJ, Talianidis I, Marioni JC, Flicek P and Odom DT

    Cell 2013;154;3;530-40

  • Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat.

    Atanur SS, Diaz AG, Maratou K, Sarkis A, Rotival M, Game L, Tschannen MR, Kaisaki PJ, Otto GW, Ma MC, Keane TM, Hummel O, Saar K, Chen W, Guryev V, Gopalakrishnan K, Garrett MR, Joe B, Citterio L, Bianchi G, McBride M, Dominiczak A, Adams DJ, Serikawa T, Flicek P, Cuppen E, Hubner N, Petretto E, Gauguier D, Kwitek A, Jacob H and Aitman TJ

    Cell 2013;154;3;691-703

  • The ancestor of extant Japanese fancy mice contributed to the mosaic genomes of classical inbred strains.

    Takada T, Ebata T, Noguchi H, Keane TM, Adams DJ, Narita T, Shin-I T, Fujisawa H, Toyoda A, Abe K, Obata Y, Sakaki Y, Moriwaki K, Fujiyama A, Kohara Y and Shiroishi T

    Genome research 2013;23;8;1329-38

  • Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes.

    White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, Salisbury J, Clare S, Ingham NJ, Podrini C, Houghton R, Estabel J, Bottomley JR, Melvin DG, Sunter D, Adams NC, Sanger Institute Mouse Genetics Project, Tannahill D, Logan DW, Macarthur DG, Flint J, Mahajan VB, Tsang SH, Smyth I, Watt FM, Skarnes WC, Dougan G, Adams DJ, Ramirez-Solis R, Bradley A and Steel KP

    Cell 2013;154;2;452-64

  • Combined sequence-based and genetic mapping analysis of complex traits in outbred rats.

    Rat Genome Sequencing and Mapping Consortium, Baud A, Hermsen R, Guryev V, Stridh P, Graham D, McBride MW, Foroud T, Calderari S, Diez M, Ockinger J, Beyeen AD, Gillett A, Abdelmagid N, Guerreiro-Cacais AO, Jagodic M, Tuncel J, Norin U, Beattie E, Huynh N, Miller WH, Koller DL, Alam I, Falak S, Osborne-Pellegrin M, Martinez-Membrives E, Canete T, Blazquez G, Vicens-Costa E, Mont-Cardona C, Diaz-Moran S, Tobena A, Hummel O, Zelenika D, Saar K, Patone G, Bauerfeind A, Bihoreau MT, Heinig M, Lee YA, Rintisch C, Schulz H, Wheeler DA, Worley KC, Muzny DM, Gibbs RA, Lathrop M, Lansu N, Toonen P, Ruzius FP, de Bruijn E, Hauser H, Adams DJ, Keane T, Atanur SS, Aitman TJ, Flicek P, Malinauskas T, Jones EY, Ekman D, Lopez-Aumatell R, Dominiczak AF, Johannesson M, Holmdahl R, Olsson T, Gauguier D, Hubner N, Fernandez-Teruel A, Cuppen E, Mott R and Flint J

    Nature genetics 2013;45;7;767-75

  • Genomic analysis of a novel spontaneous albino C57BL/6N mouse strain.

    Ryder E, Wong K, Gleeson D, Keane TM, Sethi D, Vyas S, Wardle-Jones H, Bussell JN, Houghton R, Salisbury J, Harvey N, Adams DJ, Sanger Mouse Genetics Project and Ramirez-Solis R

    Genesis (New York, N.Y. : 2000) 2013;51;7;523-8

  • Astroglial IFITM3 mediates neuronal impairments following neonatal immune challenge in mice.

    Ibi D, Nagai T, Nakajima A, Mizoguchi H, Kawase T, Tsuboi D, Kano S, Sato Y, Hayakawa M, Lange UC, Adams DJ, Surani MA, Satoh T, Sawa A, Kaibuchi K, Nabeshima T and Yamada K

    Glia 2013;61;5;679-93

  • Cancer of mice and men: old twists and new tails.

    van der Weyden L and Adams DJ

    The Journal of pathology 2013;230;1;4-16

  • Deciphering the Mechanisms of Developmental Disorders (DMDD): a new programme for phenotyping embryonic lethal mice.

    Mohun T, Adams DJ, Baldock R, Bhattacharya S, Copp AJ, Hemberger M, Houart C, Hurles ME, Robertson E, Smith JC, Weaver T and Weninger W

    Disease models & mechanisms 2013;6;3;562-6

  • RetroSeq: transposable element discovery from next-generation sequencing data.

    Keane TM, Wong K and Adams DJ

    Bioinformatics (Oxford, England) 2013;29;3;389-90

  • Jdp2 downregulates Trp53 transcription to promote leukaemogenesis in the context of Trp53 heterozygosity.

    van der Weyden L, Rust AG, McIntyre RE, Robles-Espinoza CD, del Castillo Velasco-Herrera M, Strogantsev R, Ferguson-Smith AC, McCarthy S, Keane TM, Arends MJ and Adams DJ

    Oncogene 2013;32;3;397-402

  • A comparative phenotypic and genomic analysis of C57BL/6J and C57BL/6N mouse strains.

    Simon MM, Greenaway S, White JK, Fuchs H, Gailus-Durner V, Wells S, Sorg T, Wong K, Bedu E, Cartwright EJ, Dacquin R, Djebali S, Estabel J, Graw J, Ingham NJ, Jackson IJ, Lengeling A, Mandillo S, Marvel J, Meziane H, Preitner F, Puk O, Roux M, Adams DJ, Atkins S, Ayadi A, Becker L, Blake A, Brooker D, Cater H, Champy MF, Combe R, Danecek P, di Fenza A, Gates H, Gerdin AK, Golini E, Hancock JM, Hans W, Hölter SM, Hough T, Jurdic P, Keane TM, Morgan H, Müller W, Neff F, Nicholson G, Pasche B, Roberson LA, Rozman J, Sanderson M, Santos L, Selloum M, Shannon C, Southwell A, Tocchini-Valentini GP, Vancollie VE, Westerberg H, Wurst W, Zi M, Yalcin B, Ramirez-Solis R, Steel KP, Mallon AM, de Angelis MH, Herault Y and Brown SD

    Genome biology 2013;14;7;R82

  • The genetic heterogeneity and mutational burden of engineered melanomas in zebrafish models.

    Yen J, White RM, Wedge DC, Van Loo P, de Ridder J, Capper A, Richardson J, Jones D, Raine K, Watson IR, Wu CJ, Cheng J, Martincorena I, Nik-Zainal S, Mudie L, Moreau Y, Marshall J, Ramakrishna M, Tarpey P, Shlien A, Whitmore I, Gamble S, Latimer C, Langdon E, Kaufman C, Dovey M, Taylor A, Menzies A, McLaren S, O'Meara S, Butler A, Teague J, Lister J, Chin L, Campbell P, Adams DJ, Zon LI, Patton EE, Stemple DL and Futreal PA

    Genome biology 2013;14;10;R113

  • Analysis of tumor heterogeneity and cancer gene networks using deep sequencing of MMTV-induced mouse mammary tumors.

    Klijn C, Koudijs MJ, Kool J, ten Hoeve J, Boer M, de Moes J, Akhtar W, van Miltenburg M, Vendel-Zwaagstra A, Reinders MJ, Adams DJ, van Lohuizen M, Hilkens J, Wessels LF and Jonkers J

    PloS one 2013;8;5;e62113

  • Contributions of protein-coding and regulatory change to adaptive molecular evolution in murid rodents.

    Halligan DL, Kousathanas A, Ness RW, Harr B, Eöry L, Keane TM, Adams DJ and Keightley PD

    PLoS genetics 2013;9;12;e1003995

  • Go retro and get a GRIP.

    Wong K, Adams DJ and Keane TM

    Genome biology 2013;14;3;108

  • Identification of a neuronal transcription factor network involved in medulloblastoma development.

    Lastowska M, Al-Afghani H, Al-Balool HH, Sheth H, Mercer E, Coxhead JM, Redfern CP, Peters H, Burt AD, Santibanez-Koref M, Bacon CM, Chesler L, Rust AG, Adams DJ, Williamson D, Clifford SC and Jackson MS

    Acta neuropathologica communications 2013;1;1;35

  • Mcph1-deficient mice reveal a role for MCPH1 in otitis media.

    Chen J, Ingham N, Clare S, Raisen C, Vancollie VE, Ismail O, McIntyre RE, Tsang SH, Mahajan VB, Dougan G, Adams DJ, White JK and Steel KP

    PloS one 2013;8;3;e58156

  • Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome.

    Basel-Vanagaite L, Dallapiccola B, Ramirez-Solis R, Segref A, Thiele H, Edwards A, Arends MJ, Miró X, White JK, Désir J, Abramowicz M, Dentici ML, Lepri F, Hofmann K, Har-Zahav A, Ryder E, Karp NA, Estabel J, Gerdin AK, Podrini C, Ingham NJ, Altmüller J, Nürnberg G, Frommolt P, Abdelhak S, Pasmanik-Chor M, Konen O, Kelley RI, Shohat M, Nürnberg P, Flint J, Steel KP, Hoppe T, Kubisch C, Adams DJ and Borck G

    American journal of human genetics 2012;91;6;998-1010

  • Generation of the Sotos syndrome deletion in mice.

    Migdalska AM, van der Weyden L, Ismail O, Sanger Mouse Genetics Project, Rust AG, Rashid M, White JK, Sánchez-Andrade G, Lupski JR, Logan DW, Arends MJ and Adams DJ

    Mammalian genome : official journal of the International Mammalian Genome Society 2012;23;11-12;749-57

  • Using mice to unveil the genetics of cancer resistance.

    van der Weyden L and Adams DJ

    Biochimica et biophysica acta 2012;1826;2;312-30

  • Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

    Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J, Chang DK, Cowley MJ, Gardiner BB, Song S, Harliwong I, Idrisoglu S, Nourse C, Nourbakhsh E, Manning S, Wani S, Gongora M, Pajic M, Scarlett CJ, Gill AJ, Pinho AV, Rooman I, Anderson M, Holmes O, Leonard C, Taylor D, Wood S, Xu Q, Nones K, Fink JL, Christ A, Bruxner T, Cloonan N, Kolle G, Newell F, Pinese M, Mead RS, Humphris JL, Kaplan W, Jones MD, Colvin EK, Nagrial AM, Humphrey ES, Chou A, Chin VT, Chantrill LA, Mawson A, Samra JS, Kench JG, Lovell JA, Daly RJ, Merrett ND, Toon C, Epari K, Nguyen NQ, Barbour A, Zeps N, Australian Pancreatic Cancer Genome Initiative, Kakkar N, Zhao F, Wu YQ, Wang M, Muzny DM, Fisher WE, Brunicardi FC, Hodges SE, Reid JG, Drummond J, Chang K, Han Y, Lewis LR, Dinh H, Buhay CJ, Beck T, Timms L, Sam M, Begley K, Brown A, Pai D, Panchal A, Buchner N, De Borja R, Denroche RE, Yung CK, Serra S, Onetto N, Mukhopadhyay D, Tsao MS, Shaw PA, Petersen GM, Gallinger S, Hruban RH, Maitra A, Iacobuzio-Donahue CA, Schulick RD, Wolfgang CL, Morgan RA, Lawlor RT, Capelli P, Corbo V, Scardoni M, Tortora G, Tempero MA, Mann KM, Jenkins NA, Perez-Mancera PA, Adams DJ, Largaespada DA, Wessels LF, Rust AG, Stein LD, Tuveson DA, Copeland NG, Musgrove EA, Scarpa A, Eshleman JR, Hudson TJ, Sutherland RL, Wheeler DA, Pearson JV, McPherson JD, Gibbs RA and Grimmond SM

    Nature 2012;491;7424;399-405

  • Transposon mutagenesis identifies genes that transform neural stem cells into glioma-initiating cells.

    Koso H, Takeda H, Yew CC, Ward JM, Nariai N, Ueno K, Nagasaki M, Watanabe S, Rust AG, Adams DJ, Copeland NG and Jenkins NA

    Proceedings of the National Academy of Sciences of the United States of America 2012;109;44;E2998-3007

  • Mouse large-scale phenotyping initiatives: overview of the European Mouse Disease Clinic (EUMODIC) and of the Wellcome Trust Sanger Institute Mouse Genetics Project.

    Ayadi A, Birling MC, Bottomley J, Bussell J, Fuchs H, Fray M, Gailus-Durner V, Greenaway S, Houghton R, Karp N, Leblanc S, Lengger C, Maier H, Mallon AM, Marschall S, Melvin D, Morgan H, Pavlovic G, Ryder E, Skarnes WC, Selloum M, Ramirez-Solis R, Sorg T, Teboul L, Vasseur L, Walling A, Weaver T, Wells S, White JK, Bradley A, Adams DJ, Steel KP, Hrabě de Angelis M, Brown SD and Herault Y

    Mammalian genome : official journal of the International Mammalian Genome Society 2012;23;9-10;600-10

  • Next-generation sequencing of experimental mouse strains.

    Yalcin B, Adams DJ, Flint J and Keane TM

    Mammalian genome : official journal of the International Mammalian Genome Society 2012;23;9-10;490-8

  • Loss of RASSF1A synergizes with deregulated RUNX2 signaling in tumorigenesis.

    van der Weyden L, Papaspyropoulos A, Poulogiannis G, Rust AG, Rashid M, Adams DJ, Arends MJ and O'Neill E

    Cancer research 2012;72;15;3817-27

  • The role of sphingosine-1-phosphate transporter Spns2 in immune system function.

    Nijnik A, Clare S, Hale C, Chen J, Raisen C, Mottram L, Lucas M, Estabel J, Ryder E, Adissu H, Sanger Mouse Genetics Project, Adams NC, Ramirez-Solis R, White JK, Steel KP, Dougan G and Hancock RE

    Journal of immunology (Baltimore, Md. : 1950) 2012;189;1;102-11

  • The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.

    Pérez-Mancera PA, Rust AG, van der Weyden L, Kristiansen G, Li A, Sarver AL, Silverstein KA, Grützmann R, Aust D, Rümmele P, Knösel T, Herd C, Stemple DL, Kettleborough R, Brosnan JA, Li A, Morgan R, Knight S, Yu J, Stegeman S, Collier LS, ten Hoeve JJ, de Ridder J, Klein AP, Goggins M, Hruban RH, Chang DK, Biankin AV, Grimmond SM, Australian Pancreatic Cancer Genome Initiative, Wessels LF, Wood SA, Iacobuzio-Donahue CA, Pilarsky C, Largaespada DA, Adams DJ and Tuveson DA

    Nature 2012;486;7402;266-70

  • Nuclear receptor binding protein 1 regulates intestinal progenitor cell homeostasis and tumour formation.

    Wilson CH, Crombie C, van der Weyden L, Poulogiannis G, Rust AG, Pardo M, Gracia T, Yu L, Choudhary J, Poulin GB, McIntyre RE, Winton DJ, March HN, Arends MJ, Fraser AG and Adams DJ

    The EMBO journal 2012;31;11;2486-97

  • An insertional mutagenesis screen identifies genes that cooperate with Mll-AF9 in a murine leukemogenesis model.

    Bergerson RJ, Collier LS, Sarver AL, Been RA, Lugthart S, Diers MD, Zuber J, Rappaport AR, Nixon MJ, Silverstein KA, Fan D, Lamblin AF, Wolff L, Kersey JH, Delwel R, Lowe SW, O'Sullivan MG, Kogan SC, Adams DJ and Largaespada DA

    Blood 2012;119;19;4512-23

  • IFITM3 restricts the morbidity and mortality associated with influenza.

    Everitt AR, Clare S, Pertel T, John SP, Wash RS, Smith SE, Chin CR, Feeley EM, Sims JS, Adams DJ, Wise HM, Kane L, Goulding D, Digard P, Anttila V, Baillie JK, Walsh TS, Hume DA, Palotie A, Xue Y, Colonna V, Tyler-Smith C, Dunning J, Gordon SB, GenISIS Investigators, MOSAIC Investigators, Smyth RL, Openshaw PJ, Dougan G, Brass AL and Kellam P

    Nature 2012;484;7395;519-23

  • Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma.

    Mann KM, Ward JM, Yew CC, Kovochich A, Dawson DW, Black MA, Brett BT, Sheetz TE, Dupuy AJ, Australian Pancreatic Cancer Genome Initiative, Chang DK, Biankin AV, Waddell N, Kassahn KS, Grimmond SM, Rust AG, Adams DJ, Jenkins NA and Copeland NG

    Proceedings of the National Academy of Sciences of the United States of America 2012;109;16;5934-41

  • The critical role of histone H2A-deubiquitinase Mysm1 in hematopoiesis and lymphocyte differentiation.

    Nijnik A, Clare S, Hale C, Raisen C, McIntyre RE, Yusa K, Everitt AR, Mottram L, Podrini C, Lucas M, Estabel J, Goulding D, Sanger Institute Microarray Facility, Sanger Mouse Genetics Project, Adams N, Ramirez-Solis R, White JK, Adams DJ, Hancock RE and Dougan G

    Blood 2012;119;6;1370-9

  • Cancer gene discovery in the mouse.

    McIntyre RE, van der Weyden L and Adams DJ

    Current opinion in genetics & development 2012;22;1;14-20

  • A dominantly acting murine allele of Mcm4 causes chromosomal abnormalities and promotes tumorigenesis.

    Bagley BN, Keane TM, Maklakova VI, Marshall JG, Lester RA, Cancel MM, Paulsen AR, Bendzick LE, Been RA, Kogan SC, Cormier RT, Kendziorski C, Adams DJ and Collier LS

    PLoS genetics 2012;8;11;e1003034

  • The fine-scale architecture of structural variants in 17 mouse genomes.

    Yalcin B, Wong K, Bhomra A, Goodson M, Keane TM, Adams DJ and Flint J

    Genome biology 2012;13;3;R18

  • The genomic landscape shaped by selection on transposable elements across 18 mouse strains.

    Nellåker C, Keane TM, Yalcin B, Wong K, Agam A, Belgard TG, Flint J, Adams DJ, Frankel WN and Ponting CP

    Genome biology 2012;13;6;R45

  • Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome.

    McIntyre RE, Lakshminarasimhan Chavali P, Ismail O, Carragher DM, Sanchez-Andrade G, Forment JV, Fu B, Del Castillo Velasco-Herrera M, Edwards A, van der Weyden L, Yang F, Sanger Mouse Genetics Project, Ramirez-Solis R, Estabel J, Gallagher FA, Logan DW, Arends MJ, Tsang SH, Mahajan VB, Scudamore CL, White JK, Jackson SP, Gergely F and Adams DJ

    PLoS genetics 2012;8;11;e1003022

  • High levels of RNA-editing site conservation amongst 15 laboratory mouse strains.

    Danecek P, Nellåker C, McIntyre RE, Buendia-Buendia JE, Bumpstead S, Ponting CP, Flint J, Durbin R, Keane TM and Adams DJ

    Genome biology 2012;13;4;26

  • Increased tumorigenesis associated with loss of the tumor suppressor gene Cadm1.

    van der Weyden L, Arends MJ, Rust AG, Poulogiannis G, McIntyre RE and Adams DJ

    Molecular cancer 2012;11;29

  • Modeling partial monosomy for human chromosome 21q11.2-q21.1 reveals haploinsufficient genes influencing behavior and fat deposition.

    Migdalska AM, van der Weyden L, Ismail O, White JK, Sanger Mouse Genetics Project, Sánchez-Andrade G, Logan DW, Arends MJ and Adams DJ

    PloS one 2012;7;1;e29681

  • Sequencing and characterization of the FVB/NJ mouse genome.

    Wong K, Bumpstead S, Van Der Weyden L, Reinholdt LG, Wilming LG, Adams DJ and Keane TM

    Genome biology 2012;13;8;R72

  • High-throughput semiquantitative analysis of insertional mutations in heterogeneous tumors.

    Koudijs MJ, Klijn C, van der Weyden L, Kool J, ten Hoeve J, Sie D, Prasetyanti PR, Schut E, Kas S, Whipp T, Cuppen E, Wessels L, Adams DJ and Jonkers J

    Genome research 2011;21;12;2181-9

  • Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis.

    March HN, Rust AG, Wright NA, ten Hoeve J, de Ridder J, Eldridge M, van der Weyden L, Berns A, Gadiot J, Uren A, Kemp R, Arends MJ, Wessels LF, Winton DJ and Adams DJ

    Nature genetics 2011;43;12;1202-9

  • In vivo identification of tumor- suppressive PTEN ceRNAs in an oncogenic BRAF-induced mouse model of melanoma.

    Karreth FA, Tay Y, Perna D, Ala U, Tan SM, Rust AG, DeNicola G, Webster KA, Weiss D, Perez-Mancera PA, Krauthammer M, Halaban R, Provero P, Adams DJ, Tuveson DA and Pandolfi PP

    Cell 2011;147;2;382-95

  • Mouse genomic variation and its effect on phenotypes and gene regulation.

    Keane TM, Goodstadt L, Danecek P, White MA, Wong K, Yalcin B, Heger A, Agam A, Slater G, Goodson M, Furlotte NA, Eskin E, Nellåker C, Whitley H, Cleak J, Janowitz D, Hernandez-Pliego P, Edwards A, Belgard TG, Oliver PL, McIntyre RE, Bhomra A, Nicod J, Gan X, Yuan W, van der Weyden L, Steward CA, Bala S, Stalker J, Mott R, Durbin R, Jackson IJ, Czechanski A, Guerra-Assunção JA, Donahue LR, Reinholdt LG, Payseur BA, Ponting CP, Birney E, Flint J and Adams DJ

    Nature 2011;477;7364;289-94

  • Sequence-based characterization of structural variation in the mouse genome.

    Yalcin B, Wong K, Agam A, Goodson M, Keane TM, Gan X, Nellåker C, Goodstadt L, Nicod J, Bhomra A, Hernandez-Pliego P, Whitley H, Cleak J, Dutton R, Janowitz D, Mott R, Adams DJ and Flint J

    Nature 2011;477;7364;326-9

  • A role for cohesin in T-cell-receptor rearrangement and thymocyte differentiation.

    Seitan VC, Hao B, Tachibana-Konwalski K, Lavagnolli T, Mira-Bontenbal H, Brown KE, Teng G, Carroll T, Terry A, Horan K, Marks H, Adams DJ, Schatz DG, Aragon L, Fisher AG, Krangel MS, Nasmyth K and Merkenschlager M

    Nature 2011;476;7361;467-71

  • Computational identification of insertional mutagenesis targets for cancer gene discovery.

    de Jong J, de Ridder J, van der Weyden L, Sun N, van Uitert M, Berns A, van Lohuizen M, Jonkers J, Adams DJ and Wessels LF

    Nucleic acids research 2011;39;15;e105

  • Modeling the evolution of ETV6-RUNX1-induced B-cell precursor acute lymphoblastic leukemia in mice.

    van der Weyden L, Giotopoulos G, Rust AG, Matheson LS, van Delft FW, Kong J, Corcoran AE, Greaves MF, Mullighan CG, Huntly BJ and Adams DJ

    Blood 2011;118;4;1041-51

  • Acute sensitivity of the oral mucosa to oncogenic K-ras.

    van der Weyden L, Alcolea MP, Jones PH, Rust AG, Arends MJ and Adams DJ

    The Journal of pathology 2011;224;1;22-32

  • Shotgun proteomics aids discovery of novel protein-coding genes, alternative splicing, and "resurrected" pseudogenes in the mouse genome.

    Brosch M, Saunders GI, Frankish A, Collins MO, Yu L, Wright J, Verstraten R, Adams DJ, Harrow J, Choudhary JS and Hubbard T

    Genome research 2011;21;5;756-67

  • Disruption of mouse Slx4, a regulator of structure-specific nucleases, phenocopies Fanconi anemia.

    Crossan GP, van der Weyden L, Rosado IV, Langevin F, Gaillard PH, McIntyre RE, Sanger Mouse Genetics Project, Gallagher F, Kettunen MI, Lewis DY, Brindle K, Arends MJ, Adams DJ and Patel KJ

    Nature genetics 2011;43;2;147-52

  • Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma.

    Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LF, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR and Futreal PA

    Nature 2011;469;7331;539-42

  • The mouse genetics toolkit: revealing function and mechanism.

    van der Weyden L, White JK, Adams DJ and Logan DW

    Genome biology 2011;12;6;224

  • Activation of K-RAS by co-mutation of codons 19 and 20 is transforming.

    Naguib A, Wilson CH, Adams DJ and Arends MJ

    Journal of molecular signaling 2011;6;2

  • Exome sequencing identifies a missense mutation in Isl1 associated with low penetrance otitis media in dearisch mice.

    Hilton JM, Lewis MA, Grati M, Ingham N, Pearson S, Laskowski RA, Adams DJ and Steel KP

    Genome biology 2011;12;9;R90

  • Genomics in 2011: challenges and opportunities.

    Adams DJ, Berger B, Harismendy O, Huttenhower C, Liu XS, Myers CL, Oshlack A, Rinn JL and Walhout AJ

    Genome biology 2011;12;12;137

  • Sequencing skippy: the genome sequence of an Australian kangaroo, Macropus eugenii.

    Murchison EP and Adams DJ

    Genome biology 2011;12;8;123

  • Rec8-containing cohesin maintains bivalents without turnover during the growing phase of mouse oocytes.

    Tachibana-Konwalski K, Godwin J, van der Weyden L, Champion L, Kudo NR, Adams DJ and Nasmyth K

    Genes & development 2010;24;22;2505-16

  • Analysis of the frequency of GNAS codon 201 mutations in advanced colorectal cancer.

    Idziaszczyk S, Wilson CH, Smith CG, Adams DJ and Cheadle JP

    Cancer genetics and cytogenetics 2010;202;1;67-9

  • Slingshot: a PiggyBac based transposon system for tamoxifen-inducible 'self-inactivating' insertional mutagenesis.

    Kong J, Wang F, Brenton JD and Adams DJ

    Nucleic acids research 2010;38;18;e173

  • Commercially available outbred mice for genome-wide association studies.

    Yalcin B, Nicod J, Bhomra A, Davidson S, Cleak J, Farinelli L, Østerås M, Whitley A, Yuan W, Gan X, Goodson M, Klenerman P, Satpathy A, Mathis D, Benoist C, Adams DJ, Mott R and Flint J

    PLoS genetics 2010;6;9;e1001085

  • PARK2 deletions occur frequently in sporadic colorectal cancer and accelerate adenoma development in Apc mutant mice.

    Poulogiannis G, McIntyre RE, Dimitriadi M, Apps JR, Wilson CH, Ichimura K, Luo F, Cantley LC, Wyllie AH, Adams DJ and Arends MJ

    Proceedings of the National Academy of Sciences of the United States of America 2010;107;34;15145-50

  • The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways.

    Wilson CH, McIntyre RE, Arends MJ and Adams DJ

    Oncogene 2010;29;32;4567-75

  • Using next-generation sequencing for high resolution multiplex analysis of copy number variation from nanogram quantities of DNA from formalin-fixed paraffin-embedded specimens.

    Wood HM, Belvedere O, Conway C, Daly C, Chalkley R, Bickerdike M, McKinley C, Egan P, Ross L, Hayward B, Morgan J, Davidson L, MacLennan K, Ong TK, Papagiannopoulos K, Cook I, Adams DJ, Taylor GR and Rabbitts P

    Nucleic acids research 2010;38;14;e151

  • CHD7 targets active gene enhancer elements to modulate ES cell-specific gene expression.

    Schnetz MP, Handoko L, Akhtar-Zaidi B, Bartels CF, Pereira CF, Fisher AG, Adams DJ, Flicek P, Crawford GE, Laframboise T, Tesar P, Wei CL and Scacheri PC

    PLoS genetics 2010;6;7;e1001023

  • 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers.

    Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der Gulden H, Hiddingh S, Thanasoula M, Kulkarni A, Yang Q, Haffty BG, Tommiska J, Blomqvist C, Drapkin R, Adams DJ, Nevanlinna H, Bartek J, Tarsounas M, Ganesan S and Jonkers J

    Nature structural & molecular biology 2010;17;6;688-95

  • Copy number variant detection in inbred strains from short read sequence data.

    Simpson JT, McIntyre RE, Adams DJ and Durbin R

    Bioinformatics (Oxford, England) 2010;26;4;565-7

  • Novel candidate cancer genes identified by a large-scale cross-species comparative oncogenomics approach.

    Mattison J, Kool J, Uren AG, de Ridder J, Wessels L, Jonkers J, Bignell GR, Butler A, Rust AG, Brosch M, Wilson CH, van der Weyden L, Largaespada DA, Stratton MR, Futreal PA, van Lohuizen M, Berns A, Collier LS, Hubbard T and Adams DJ

    Cancer research 2010;70;3;883-95

  • Genome-wide end-sequenced BAC resources for the NOD/MrkTac() and NOD/ShiLtJ() mouse genomes.

    Steward CA, Humphray S, Plumb B, Jones MC, Quail MA, Rice S, Cox T, Davies R, Bonfield J, Keane TM, Nefedov M, de Jong PJ, Lyons P, Wicker L, Todd J, Hayashizaki Y, Gulban O, Danska J, Harrow J, Hubbard T, Rogers J and Adams DJ

    Genomics 2010;95;2;105-10

  • Insertional mutagenesis in mice deficient for p15Ink4b, p16Ink4a, p21Cip1, and p27Kip1 reveals cancer gene interactions and correlations with tumor phenotypes.

    Kool J, Uren AG, Martins CP, Sie D, de Ridder J, Turner G, van Uitert M, Matentzoglu K, Lagcher W, Krimpenfort P, Gadiot J, Pritchard C, Lenz J, Lund AH, Jonkers J, Rogers J, Adams DJ, Wessels L, Berns A and van Lohuizen M

    Cancer research 2010;70;2;520-31

  • A high-throughput pharmaceutical screen identifies compounds with specific toxicity against BRCA2-deficient tumors.

    Evers B, Schut E, van der Burg E, Braumuller TM, Egan DA, Holstege H, Edser P, Adams DJ, Wade-Martins R, Bouwman P and Jonkers J

    Clinical cancer research : an official journal of the American Association for Cancer Research 2010;16;1;99-108

  • Identification of networks of co-occurring, tumor-related DNA copy number changes using a genome-wide scoring approach.

    Klijn C, Bot J, Adams DJ, Reinders M, Wessels L and Jonkers J

    PLoS computational biology 2010;6;1;e1000631

  • Ectodomains of the LDL receptor-related proteins LRP1b and LRP4 have anchorage independent functions in vivo.

    Dietrich MF, van der Weyden L, Prosser HM, Bradley A, Herz J and Adams DJ

    PloS one 2010;5;4;e9960

  • Somatic structural rearrangements in genetically engineered mouse mammary tumors.

    Varela I, Klijn C, Stephens PJ, Mudie LJ, Stebbings L, Galappaththige D, van der Gulden H, Schut E, Klarenbeek S, Campbell PJ, Wessels LF, Stratton MR, Jonkers J, Futreal PA and Adams DJ

    Genome biology 2010;11;10;R100

  • The IFITM proteins mediate cellular resistance to influenza A H1N1 virus, West Nile virus, and dengue virus.

    Brass AL, Huang IC, Benita Y, John SP, Krishnan MN, Feeley EM, Ryan BJ, Weyer JL, van der Weyden L, Fikrig E, Adams DJ, Xavier RJ, Farzan M and Elledge SJ

    Cell 2009;139;7;1243-54

  • Cancer gene discovery in mouse and man.

    Mattison J, van der Weyden L, Hubbard T and Adams DJ

    Biochimica et biophysica acta 2009;1796;2;140-61

  • Discovery of candidate disease genes in ENU-induced mouse mutants by large-scale sequencing, including a splice-site mutation in nucleoredoxin.

    Boles MK, Wilkinson BM, Wilming LG, Liu B, Probst FJ, Harrow J, Grafham D, Hentges KE, Woodward LP, Maxwell A, Mitchell K, Risley MD, Johnson R, Hirschi K, Lupski JR, Funato Y, Miki H, Marin-Garcia P, Matthews L, Coffey AJ, Parker A, Hubbard TJ, Rogers J, Bradley A, Adams DJ and Justice MJ

    PLoS genetics 2009;5;12;e1000759

  • Whole-body sleeping beauty mutagenesis can cause penetrant leukemia/lymphoma and rare high-grade glioma without associated embryonic lethality.

    Collier LS, Adams DJ, Hackett CS, Bendzick LE, Akagi K, Davies MN, Diers MD, Rodriguez FJ, Bender AM, Tieu C, Matise I, Dupuy AJ, Copeland NG, Jenkins NA, Hodgson JG, Weiss WA, Jenkins RB and Largaespada DA

    Cancer research 2009;69;21;8429-37

  • Next-generation sequencing of vertebrate experimental organisms.

    Turner DJ, Keane TM, Sudbery I and Adams DJ

    Mammalian genome : official journal of the International Mammalian Genome Society 2009;20;6;327-38

  • Megaoesophagus in Rassf1a-null mice.

    van der Weyden L, Happerfield L, Arends MJ and Adams DJ

    International journal of experimental pathology 2009;90;2;101-8

  • A high-throughput splinkerette-PCR method for the isolation and sequencing of retroviral insertion sites.

    Uren AG, Mikkers H, Kool J, van der Weyden L, Lund AH, Wilson CH, Rance R, Jonkers J, van Lohuizen M, Berns A and Adams DJ

    Nature protocols 2009;4;5;789-98

  • Deep short-read sequencing of chromosome 17 from the mouse strains A/J and CAST/Ei identifies significant germline variation and candidate genes that regulate liver triglyceride levels.

    Sudbery I, Stalker J, Simpson JT, Keane T, Rust AG, Hurles ME, Walter K, Lynch D, Teboul L, Brown SD, Li H, Ning Z, Nadeau JH, Croniger CM, Durbin R and Adams DJ

    Genome biology 2009;10;10;R112

  • iMapper: a web application for the automated analysis and mapping of insertional mutagenesis sequence data against Ensembl genomes.

    Kong J, Zhu F, Stalker J and Adams DJ

    Bioinformatics (Oxford, England) 2008;24;24;2923-5

  • Contemporary approaches for modifying the mouse genome.

    Adams DJ and van der Weyden L

    Physiological genomics 2008;34;3;225-38

  • Normal germ line establishment in mice carrying a deletion of the Ifitm/Fragilis gene family cluster.

    Lange UC, Adams DJ, Lee C, Barton S, Schneider R, Bradley A and Surani MA

    Molecular and cellular biology 2008;28;15;4688-96

  • Loss of Rassf1a cooperates with Apc(Min) to accelerate intestinal tumourigenesis.

    van der Weyden L, Arends MJ, Dovey OM, Harrison HL, Lefebvre G, Conte N, Gergely FV, Bradley A and Adams DJ

    Oncogene 2008;27;32;4503-8

  • Large-scale mutagenesis in p19(ARF)- and p53-deficient mice identifies cancer genes and their collaborative networks.

    Uren AG, Kool J, Matentzoglu K, de Ridder J, Mattison J, van Uitert M, Lagcher W, Sie D, Tanger E, Cox T, Reinders M, Hubbard TJ, Rogers J, Jonkers J, Wessels L, Adams DJ, van Lohuizen M and Berns A

    Cell 2008;133;4;727-41

  • Renin enhancer is crucial for full response in Renin expression to an in vivo stimulus.

    Markus MA, Goy C, Adams DJ, Lovicu FJ and Morris BJ

    Hypertension 2007;50;5;933-8

  • The Ras-association domain family (RASSF) members and their role in human tumourigenesis.

    van der Weyden L and Adams DJ

    Biochimica et biophysica acta 2007;1776;1;58-85

  • Renin enhancer is critical for control of renin gene expression and cardiovascular function.

    Adams DJ, Head GA, Markus MA, Lovicu FJ, van der Weyden L, Köntgen F, Arends MJ, Thiru S, Mayorov DN and Morris BJ

    The Journal of biological chemistry 2006;281;42;31753-61

  • WT1 interacts with the splicing protein RBM4 and regulates its ability to modulate alternative splicing in vivo.

    Markus MA, Heinrich B, Raitskin O, Adams DJ, Mangs H, Goy C, Ladomery M, Sperling R, Stamm S and Morris BJ

    Experimental cell research 2006;312;17;3379-88

  • Functional knockout of the matrilin-3 gene causes premature chondrocyte maturation to hypertrophy and increases bone mineral density and osteoarthritis.

    van der Weyden L, Wei L, Luo J, Yang X, Birk DE, Adams DJ, Bradley A and Chen Q

    The American journal of pathology 2006;169;2;515-27

  • TranscriptSNPView: a genome-wide catalog of mouse coding variation.

    Cunningham F, Rios D, Griffiths M, Smith J, Ning Z, Cox T, Flicek P, Marin-Garcin P, Herrero J, Rogers J, van der Weyden L, Bradley A, Birney E and Adams DJ

    Nature genetics 2006;38;8;853

  • Geminin is essential to prevent endoreduplication and to form pluripotent cells during mammalian development.

    Gonzalez MA, Tachibana KE, Adams DJ, van der Weyden L, Hemberger M, Coleman N, Bradley A and Laskey RA

    Genes & development 2006;20;14;1880-4

  • Loss of TSLC1 causes male infertility due to a defect at the spermatid stage of spermatogenesis.

    van der Weyden L, Arends MJ, Chausiaux OE, Ellis PJ, Lange UC, Surani MA, Affara N, Murakami Y, Adams DJ and Bradley A

    Molecular and cellular biology 2006;26;9;3595-609

  • DNA sequence of human chromosome 17 and analysis of rearrangement in the human lineage.

    Zody MC, Garber M, Adams DJ, Sharpe T, Harrow J, Lupski JR, Nicholson C, Searle SM, Wilming L, Young SK, Abouelleil A, Allen NR, Bi W, Bloom T, Borowsky ML, Bugalter BE, Butler J, Chang JL, Chen CK, Cook A, Corum B, Cuomo CA, de Jong PJ, DeCaprio D, Dewar K, FitzGerald M, Gilbert J, Gibson R, Gnerre S, Goldstein S, Grafham DV, Grocock R, Hafez N, Hagopian DS, Hart E, Norman CH, Humphray S, Jaffe DB, Jones M, Kamal M, Khodiyar VK, LaButti K, Laird G, Lehoczky J, Liu X, Lokyitsang T, Loveland J, Lui A, Macdonald P, Major JE, Matthews L, Mauceli E, McCarroll SA, Mihalev AH, Mudge J, Nguyen C, Nicol R, O'Leary SB, Osoegawa K, Schwartz DC, Shaw-Smith C, Stankiewicz P, Steward C, Swarbreck D, Venkataraman V, Whittaker CA, Yang X, Zimmer AR, Bradley A, Hubbard T, Birren BW, Rogers J, Lander ES and Nusbaum C

    Nature 2006;440;7087;1045-9

  • XE7: a novel splicing factor that interacts with ASF/SF2 and ZNF265.

    Mangs AH, Speirs HJ, Goy C, Adams DJ, Markus MA and Morris BJ

    Nucleic acids research 2006;34;17;4976-86

  • A genome-wide, end-sequenced 129Sv BAC library resource for targeting vector construction.

    Adams DJ, Quail MA, Cox T, van der Weyden L, Gorick BD, Su Q, Chan WI, Davies R, Bonfield JK, Law F, Humphray S, Plumb B, Liu P, Rogers J and Bradley A

    Genomics 2005;86;6;753-8

  • The RASSF1A isoform of RASSF1 promotes microtubule stability and suppresses tumorigenesis.

    van der Weyden L, Tachibana KK, Gonzalez MA, Adams DJ, Ng BL, Petty R, Venkitaraman AR, Arends MJ and Bradley A

    Molecular and cellular biology 2005;25;18;8356-67

  • Complex haplotypes, copy number polymorphisms and coding variation in two recently divergent mouse strains.

    Adams DJ, Dermitzakis ET, Cox T, Smith J, Davies R, Banerjee R, Bonfield J, Mullikin JC, Chung YJ, Rogers J and Bradley A

    Nature genetics 2005;37;5;532-6

  • Null and conditional semaphorin 3B alleles using a flexible puroDeltatk loxP/FRT vector.

    van der Weyden L, Adams DJ, Harris LW, Tannahill D, Arends MJ and Bradley A

    Genesis (New York, N.Y. : 2000) 2005;41;4;171-8

  • BRCTx is a novel, highly conserved RAD18-interacting protein.

    Adams DJ, van der Weyden L, Gergely FV, Arends MJ, Ng BL, Tannahill D, Kanaar R, Markus A, Morris BJ and Bradley A

    Molecular and cellular biology 2005;25;2;779-88

  • cAMP controls human renin mRNA stability via specific RNA-binding proteins.

    Morris BJ, Adams DJ, Beveridge DJ, van der Weyden L, Mangs H and Leedman PJ

    Acta physiologica Scandinavica 2004;181;4;369-73

  • Mutagenic insertion and chromosome engineering resource (MICER).

    Adams DJ, Biggs PJ, Cox T, Davies R, van der Weyden L, Jonkers J, Smith J, Plumb B, Taylor R, Nishijima I, Yu Y, Rogers J and Bradley A

    Nature genetics 2004;36;8;867-71

  • Tools for targeted manipulation of the mouse genome.

    van der Weyden L, Adams DJ and Bradley A

    Physiological genomics 2002;11;3;133-64

  • Induced mitotic recombination: a switch in time.

    Adams DJ and Bradley A

    Nature genetics 2002;30;1;6-7

Team

Team members

David Adams
Senior Group Leader
Clara Alsinet-Armengol
Postdoctoral Fellow
Martin Del Castillo Velasco Herrera
PhD Student
Stefan Dentro
PhD Student
Richard Gunning
PhD Student
Marco Ranzani
Postdoctoral Fellow
Daniela Robles Espinoza
Postdoctoral Fellow
Marcela Sjoberg
Postdoctoral Fellow
Louise Van Der Weyden
Senior Staff Scientist
Chi Wong
Postdoctoral Fellow
Robin van der Weide
MSc. intern

David Adams

- Senior Group Leader

BSc (Hons), University of Technology, Sydney, 1996. PhD, University of Sydney, 2001. Senior Group Leader (& CR-UK Senior Fellow), 2006-present.

Research

I'm interested in finding cancer genes through sequencing and genetic screens and using model systems (mainly mouse and cells in culture) to understand how these genes work.

References

  • The mutational landscapes of genetic and chemical models of Kras-driven lung cancer.

    Westcott PM, Halliwill KD, To MD, Rashid M, Rust AG, Keane TM, Delrosario R, Jen KY, Gurley KE, Kemp CJ, Fredlund E, Quigley DA, Adams DJ and Balmain A

    1] Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California 94158, USA [2] Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California 94158, USA.

    Next-generation sequencing of human tumours has refined our understanding of the mutational processes operative in cancer initiation and progression, yet major questions remain regarding the factors that induce driver mutations and the processes that shape mutation selection during tumorigenesis. Here we performed whole-exome sequencing on adenomas from three mouse models of non-small-cell lung cancer, which were induced either by exposure to carcinogens (methyl-nitrosourea (MNU) and urethane) or by genetic activation of Kras (Kras(LA2)). Although the MNU-induced tumours carried exactly the same initiating mutation in Kras as seen in the Kras(LA2) model (G12D), MNU tumours had an average of 192 non-synonymous, somatic single-nucleotide variants, compared with only six in tumours from the Kras(LA2) model. By contrast, the Kras(LA2) tumours exhibited a significantly higher level of aneuploidy and copy number alterations compared with the carcinogen-induced tumours, suggesting that carcinogen-induced and genetically engineered models lead to tumour development through different routes. The wild-type allele of Kras has been shown to act as a tumour suppressor in mouse models of non-small-cell lung cancer. We demonstrate that urethane-induced tumours from wild-type mice carry mostly (94%) Kras Q61R mutations, whereas those from Kras heterozygous animals carry mostly (92%) Kras Q61L mutations, indicating a major role for germline Kras status in mutation selection during initiation. The exome-wide mutation spectra in carcinogen-induced tumours overwhelmingly display signatures of the initiating carcinogen, while adenocarcinomas acquire additional C > T mutations at CpG sites. These data provide a basis for understanding results from human tumour genome sequencing, which has identified two broad categories of tumours based on the relative frequency of single-nucleotide variations and copy number alterations, and underline the importance of carcinogen models for understanding the complex mutation spectra seen in human cancers.

    Funded by: Cancer Research UK; NCI NIH HHS: F31 CA180669, F31 CA180715, R01 CA111834, U01 CA084244, U01 CA141455, U01 CA176287, U01 CA84244, UO1 CA176287; NIGMS NIH HHS: T32 GM007175, T32GM007175; Wellcome Trust

    Nature 2015;517;7535;489-92

  • POT1 loss-of-function variants predispose to familial melanoma.

    Robles-Espinoza CD, Harland M, Ramsay AJ, Aoude LG, Quesada V, Ding Z, Pooley KA, Pritchard AL, Tiffen JC, Petljak M, Palmer JM, Symmons J, Johansson P, Stark MS, Gartside MG, Snowden H, Montgomery GW, Martin NG, Liu JZ, Choi J, Makowski M, Brown KM, Dunning AM, Keane TM, López-Otín C, Gruis NA, Hayward NK, Bishop DT, Newton-Bishop JA and Adams DJ

    1] Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK. [2].

    Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.

    Funded by: Cancer Research UK: 10589, 13031, A10123, C1287/A9540, C588/A10589, C588/A4994, C8197/A10123; Wellcome Trust: WT091310, WT098051

    Nature genetics 2014;46;5;478-81

  • Inactivating CUX1 mutations promote tumorigenesis.

    Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C, Alexandrov LB, Tiffen JC, Kober C, Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium, Green AR, Massie CE, Nangalia J, Lempidaki S, Döhner H, Döhner K, Bray SJ, McDermott U, Papaemmanuil E, Campbell PJ and Adams DJ

    1] Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. [2] Department of Haematology, University of Cambridge, Hills Road, Cambridge, UK.

    A major challenge in cancer genetics is to determine which low-frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers and find inactivating mutations in the homeodomain transcription factor gene CUX1 (cut-like homeobox 1) in ~1-5% of various tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss. In parallel, we validate CUX1 as a bona fide tumor suppressor using mouse transposon-mediated insertional mutagenesis and Drosophila cancer models. We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. Thus, our complementary approaches identify CUX1 as a pan-driver of tumorigenesis and uncover a potential strategy for treating CUX1-mutant tumors.

    Funded by: Cancer Research UK: 13031, 16629, A13031, A14356, A6542, A6997; Medical Research Council: G0800034; Wellcome Trust: 079249, 082356, 088340, 093867, 100140

    Nature genetics 2014;46;1;33-8

  • The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma.

    Pérez-Mancera PA, Rust AG, van der Weyden L, Kristiansen G, Li A, Sarver AL, Silverstein KA, Grützmann R, Aust D, Rümmele P, Knösel T, Herd C, Stemple DL, Kettleborough R, Brosnan JA, Li A, Morgan R, Knight S, Yu J, Stegeman S, Collier LS, ten Hoeve JJ, de Ridder J, Klein AP, Goggins M, Hruban RH, Chang DK, Biankin AV, Grimmond SM, Australian Pancreatic Cancer Genome Initiative, Wessels LF, Wood SA, Iacobuzio-Donahue CA, Pilarsky C, Largaespada DA, Adams DJ and Tuveson DA

    Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge CB2 0RE, UK.

    Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.

    Funded by: Cancer Research UK: 13031; NCI NIH HHS: 2P50CA101955, CA106610, CA122183, CA128920, CA62924, K01 CA122183, K01 CA122183-05, P50 CA062924, P50 CA101955, P50CA62924; Wellcome Trust

    Nature 2012;486;7402;266-70

  • Mouse genomic variation and its effect on phenotypes and gene regulation.

    Keane TM, Goodstadt L, Danecek P, White MA, Wong K, Yalcin B, Heger A, Agam A, Slater G, Goodson M, Furlotte NA, Eskin E, Nellåker C, Whitley H, Cleak J, Janowitz D, Hernandez-Pliego P, Edwards A, Belgard TG, Oliver PL, McIntyre RE, Bhomra A, Nicod J, Gan X, Yuan W, van der Weyden L, Steward CA, Bala S, Stalker J, Mott R, Durbin R, Jackson IJ, Czechanski A, Guerra-Assunção JA, Donahue LR, Reinholdt LG, Payseur BA, Ponting CP, Birney E, Flint J and Adams DJ

    The Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, UK.

    We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.

    Funded by: Biotechnology and Biological Sciences Research Council: BB/F022697/1; Cancer Research UK: A6997; Medical Research Council: G0800024, MC_U127561112, MC_U137761446; NHLBI NIH HHS: K25 HL080079; NLM NIH HHS: 2T15LM007359; Wellcome Trust: 077192, 079912, 082356, 083573, 083573/Z/07/Z, 085906, 085906/Z/08/Z, 090532

    Nature 2011;477;7364;289-94

Clara Alsinet-Armengol

- Postdoctoral Fellow

2008-2013 UNIVERSITY OF BARCELONA • PhD in Biomedicine. Thesis title: Characterization of driver pathways in hepatocellular carcinoma through genomic profiling and animal models. Qualification: Cum Laude and Doctorate Extraordinary award 2013-2014. 2006-2008 UNIVERSITY OF BARCELONA • Graduate studies on Molecular and Cellular Biology. 2005-2006 UNIVERSITY OF CALIFORNIA - UCDavis • EAP student (Education Abroad Program). 2001-2006 AUTONOMOUS UNIVERSITY OF BARCELONA • Major in Biotechnology, BSc.

Research

High-throughput sequencing efforts are uncovering the mutation profiles associated to cancer in a comprehensive and unbiased fashion. Nevertheless, further analyses of the identified alterations are necessary to highlight those genes implicated in disease development, as well as, those with therapeutical potential. Recently, we generated a list of candidate genes commonly truncated based on the analysis of >7500 cancer samples across 28 tissues. Therefore, we are generating a panel of isogenic iPS cell lines to perform high-throughput genetic and drug screenings. Overall, this study will identify molecular interactions of the selected cancer-related genes thus revealing potential new roles and candidate therapies.

References

  • Unique Genomic Profile of Fibrolamellar Hepatocellular Carcinoma.

    Cornella H, Alsinet C, Sayols S, Zhang Z, Hao K, Cabellos L, Hoshida Y, Villanueva A, Thung S, Ward SC, Rodriguez-Carunchio L, Vila-Casadesús M, Imbeaud S, Lachenmayer A, Quaglia A, Nagorney DM, Minguez B, Carrilho F, Roberts LR, Waxman S, Mazzaferro V, Schwartz M, Esteller M, Heaton ND, Zucman-Rossi J and Llovet JM

    HCC Translational Research Laboratory, Barcelona Clinic Liver Cancer Group, Liver Unit, Pathology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer, CIBERehd, Hospital Clínic, Universitat de Barcelona, Catalonia, Spain.

    Background & aims: Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary hepatic cancer that develops in children and young adults without cirrhosis. Little is known about its pathogenesis, and it can be treated only with surgery. We performed an integrative genomic analysis of a large series of patients with FLC to identify associated genetic factors.

    Methods: By using 78 clinically annotated FLC samples, we performed whole-transcriptome (n = 58), single-nucleotide polymorphism array (n = 41), and next-generation sequencing (n = 48) analyses; we also assessed the prevalence of the DNAJB1-PRKACA fusion transcript associated with this cancer (n = 73). We performed class discovery using non-negative matrix factorization, and functional annotation using gene-set enrichment analyses, nearest template prediction, ingenuity pathway analyses, and immunohistochemistry. The genomic identification of significant targets in a cancer algorithm was used to identify chromosomal aberrations, MuTect and VarScan2 were used to identify somatic mutations, and the random survival forest was used to determine patient prognoses. Findings were validated in an independent cohort.

    Results: Unsupervised gene expression clustering showed 3 robust molecular classes of tumors: the proliferation class (51% of samples) had altered expression of genes that regulate proliferation and mammalian target of rapamycin signaling activation; the inflammation class (26% of samples) had altered expression of genes that regulate inflammation and cytokine production; and the unannotated class (23% of samples) had a gene expression signature that was not associated previously with liver tumors. Expression of genes that regulate neuroendocrine function, as well as histologic markers of cholangiocytes and hepatocytes, were detected in all 3 classes. FLCs had few copy number variations; the most frequent were focal amplification at 8q24.3 (in 12.5% of samples), and deletions at 19p13 (in 28% of samples) and 22q13.32 (in 25% of samples). The DNAJB1-PRKACA fusion transcript was detected in 79% of samples. FLC samples also contained mutations in cancer-related genes such as BRCA2 (in 4.2% of samples), which are uncommon in liver neoplasms. However, FLCs did not contain mutations most commonly detected in liver cancers. We identified an 8-gene signature that predicted survival of patients with FLC.

    Conclusions: In a genomic analysis of 78 FLC samples, we identified 3 classes based on gene expression profiles. FLCs contain mutations and chromosomal aberrations not previously associated with liver cancer, and almost 80% contain the DNAJB1-PRKACA fusion transcript. By using this information, we identified a gene signature that is associated with patient survival time.

    Gastroenterology 2014

  • UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma.

    Mudbhary R, Hoshida Y, Chernyavskaya Y, Jacob V, Villanueva A, Fiel MI, Chen X, Kojima K, Thung S, Bronson RT, Lachenmayer A, Revill K, Alsinet C, Sachidanandam R, Desai A, SenBanerjee S, Ukomadu C, Llovet JM and Sadler KC

    Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Department of Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Graduate School of Biological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.

    Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an essential regulator of DNA methylation that is highly expressed in many cancers. Here, we use transgenic zebrafish, cultured cells, and human tumors to demonstrate that UHRF1 is an oncogene. UHRF1 overexpression in zebrafish hepatocytes destabilizes and delocalizes Dnmt1 and causes DNA hypomethylation and Tp53-mediated senescence. Hepatocellular carcinoma (HCC) emerges when senescence is bypassed. tp53 mutation both alleviates senescence and accelerates tumor onset. Human HCCs recapitulate this paradigm, as UHRF1 overexpression defines a subclass of aggressive HCCs characterized by genomic instability, TP53 mutation, and abrogation of the TP53-mediated senescence program. We propose that UHRF1 overexpression is a mechanism underlying DNA hypomethylation in cancer cells and that senescence is a primary means of restricting tumorigenesis due to epigenetic disruption.

    Funded by: NCI NIH HHS: 5P30CA006516-45, P30 CA006516, T32 CA078207, T32CA078207-14; NHGRI NIH HHS: R21 HG007394; NIDDK NIH HHS: 1R01DK076986, 1R01DK099558, 5R01DK080789-02, F30 DK094503, F30DK094503, R01 DK076986, R01 DK080789, R01 DK099558

    Cancer cell 2014;25;2;196-209

  • One patient, two lesions, two oncogenic drivers of gastric cancer.

    Alsinet C, Ranzani M and Adams DJ

    Deep-sequencing of a primary tumor and metastasis from a single patient, and functional validation in culture, reveals that TGFBR2 and FGFR2 act as drivers of gastric cancer.

    Funded by: Cancer Research UK: 13031

    Genome biology 2014;15;8;444

  • Genetically engineered mouse models: future tools to predict clinical trial results in oncology?

    Alsinet C, Cornella H and Villanueva A

    Future oncology (London, England) 2013;9;6;767-70

  • Notch signaling is activated in human hepatocellular carcinoma and induces tumor formation in mice.

    Villanueva A, Alsinet C, Yanger K, Hoshida Y, Zong Y, Toffanin S, Rodriguez-Carunchio L, Solé M, Thung S, Stanger BZ and Llovet JM

    HCC Translational Research Laboratory, Barcelona-Clínic Liver Cancer Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Catalonia, Spain.

    Background & aims: The Notch signaling pathway is activated in leukemia and solid tumors (such as lung cancer), but little is known about its role in liver cancer.

    Methods: The intracellular domain of Notch was conditionally expressed in hepatoblasts and their progeny (hepatocytes and cholangiocytes) in mice. This was achieved through Cre expression under the control of an albumin and α-fetoprotein (AFP) enhancer and promoter (AFP-Notch intracellular domain [NICD]). We used comparative functional genomics to integrate transcriptome data from AFP-NICD mice and human hepatocellular carcinoma (HCC) samples (n = 683). A Notch gene signature was generated using the nearest template prediction method.

    Results: AFP-NICD mice developed HCC with 100% penetrance when they were 12 months old. Activation of Notch signaling correlated with activation of 3 promoters of insulin-like growth factor 2; these processes appeared to contribute to hepatocarcinogenesis. Comparative functional genomic analysis identified a signature of Notch activation in 30% of HCC samples from patients. These samples had altered expression in Notch pathway genes and activation of insulin-like growth factor signaling, despite a low frequency of mutations in regions of NOTCH1 associated with cancer. Blocking Notch signaling in liver cancer cells with the Notch activation signature using γ-secretase inhibitors or by expressing a dominant negative form of mastermind-like 1 reduced their proliferation in vitro.

    Conclusions: Notch signaling is activated in human HCC samples and promotes formation of liver tumors in mice. The Notch signature is a biomarker of response to Notch inhibition in vitro.

    Funded by: NIDDK NIH HHS: 1R01DK076986, DP2-DK083111, R01 DK076986, R01-DK083355

    Gastroenterology 2012;143;6;1660-1669.e7

  • Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by sorafenib.

    Lachenmayer A, Alsinet C, Savic R, Cabellos L, Toffanin S, Hoshida Y, Villanueva A, Minguez B, Newell P, Tsai HW, Barretina J, Thung S, Ward SC, Bruix J, Mazzaferro V, Schwartz M, Friedman SL and Llovet JM

    Mount Sinai Liver Cancer Program, Mount Sinai School of Medicine, New York, NY 10029, USA.

    Purpose: Hepatocellular carcinoma (HCC) is a heterogeneous cancer with active Wnt signaling. Underlying biologic mechanisms remain unclear and no drug targeting this pathway has been approved to date. We aimed to characterize Wnt-pathway aberrations in HCC patients, and to investigate sorafenib as a potential Wnt modulator in experimental models of liver cancer.

    Experimental design: The Wnt-pathway was assessed using mRNA (642 HCCs and 21 liver cancer cell lines) and miRNA expression data (89 HCCs), immunohistochemistry (108 HCCs), and CTNNB1-mutation data (91 HCCs). Effects of sorafenib on Wnt signaling were evaluated in four liver cancer cell lines with active Wnt signaling and a tumor xenograft model.

    Results: Evidence for Wnt activation was observed for 315 (49.1%) cases, and was further classified as CTNNB1 class (138 cases [21.5%]) or Wnt-TGFβ class (177 cases [27.6%]). CTNNB1 class was characterized by upregulation of liver-specific Wnt-targets, nuclear β-catenin and glutamine-synthetase immunostaining, and enrichment of CTNNB1-mutation-signature, whereas Wnt-TGFβ class was characterized by dysregulation of classical Wnt-targets and the absence of nuclear β-catenin. Sorafenib decreased Wnt signaling and β-catenin protein in HepG2 (CTNNB1 class), SNU387 (Wnt-TGFβ class), SNU398 (CTNNB1-mutation), and Huh7 (lithium-chloride-pathway activation) cell lines. In addition, sorafenib attenuated expression of liver-related Wnt-targets GLUL, LGR5, and TBX3. The suppressive effect on CTNNB1 class-specific Wnt-pathway activation was validated in vivo using HepG2 xenografts in nude mice, accompanied by decreased tumor volume and increased survival of treated animals.

    Conclusions: Distinct dysregulation of Wnt-pathway constituents characterize two different Wnt-related molecular classes (CTNNB1 and Wnt-TGFβ), accounting for half of all HCC patients. Sorafenib modulates β-catenin/Wnt signaling in experimental models that harbor the CTNNB1 class signature.

    Funded by: NIDDK NIH HHS: 1R01DK076986-01, 1R01DK37340, 1R01DK56621, R01 DK037340, R01 DK056621, R01 DK076986

    Clinical cancer research : an official journal of the American Association for Cancer Research 2012;18;18;4997-5007

  • IGF activation in a molecular subclass of hepatocellular carcinoma and pre-clinical efficacy of IGF-1R blockage.

    Tovar V, Alsinet C, Villanueva A, Hoshida Y, Chiang DY, Solé M, Thung S, Moyano S, Toffanin S, Mínguez B, Cabellos L, Peix J, Schwartz M, Mazzaferro V, Bruix J and Llovet JM

    HCC Translational Laboratory, BCLC Group, Liver Unit and Pathology Department, Hospital Clínic, CIBERehd, IDIBAPS, c/Villarroel 170, Catalonia, Spain.

    Background & aims: IGF signaling has a relevant role in a variety of human malignancies. We analyzed the underlying molecular mechanisms of IGF signaling activation in early hepatocellular carcinoma (HCC; BCLC class 0 or A) and assessed novel targeted therapies blocking this pathway.

    Methods: An integrative molecular dissection of the axis was conducted in a cohort of 104 HCCs analyzing gene and miRNA expression, structural aberrations, and protein activation. The therapeutic potential of a selective IGF-1R inhibitor, the monoclonal antibody A12, was assessed in vitro and in a xenograft model of HCC.

    Results: Activation of the IGF axis was observed in 21% of early HCCs. Several molecular aberrations were identified, such as overexpression of IGF2 -resulting from reactivation of fetal promoters P3 and P4-, IGFBP3 downregulation and allelic losses of IGF2R (25% of cases). A gene signature defining IGF-1R activation was developed. Overall, activation of IGF signaling in HCC was significantly associated with mTOR signaling (p=0.035) and was clearly enriched in the Proliferation subclass of the molecular classification of HCC (p=0.001). We also found an inverse correlation between IGF activation and miR-100/miR-216 levels (FDR<0.05). In vitro studies showed that A12-induced abrogation of IGF-1R activation and downstream signaling significantly decreased cell viability and proliferation. In vivo, A12 delayed tumor growth and prolonged survival, reducing proliferation rates and inducing apoptosis.

    Conclusions: Integrative genomic analysis showed enrichment of activation of IGF signaling in the Proliferation subclass of HCC. Effective blockage of IGF signaling with A12 provides the rationale for testing this therapy in clinical trials.

    Funded by: NIDDK NIH HHS: R01 DK076986

    Journal of hepatology 2010;52;4;550-9

  • Pivotal role of mTOR signaling in hepatocellular carcinoma.

    Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, Tovar V, Roayaie S, Minguez B, Sole M, Battiston C, Van Laarhoven S, Fiel MI, Di Feo A, Hoshida Y, Yea S, Toffanin S, Ramos A, Martignetti JA, Mazzaferro V, Bruix J, Waxman S, Schwartz M, Meyerson M, Friedman SL and Llovet JM

    Mount Sinai Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.

    Background &amp; aims: The advent of targeted therapies in hepatocellular carcinoma (HCC) has underscored the importance of pathway characterization to identify novel molecular targets for treatment. We evaluated mTOR signaling in human HCC, as well as the antitumoral effect of a dual-level blockade of the mTOR pathway.

    Methods: The mTOR pathway was assessed using integrated data from mutation analysis (direct sequencing), DNA copy number changes (SNP-array), messenger RNA levels (quantitative reverse-transcription polymerase chain reaction and gene expression microarray), and protein activation (immunostaining) in 351 human samples [HCC (n = 314) and nontumoral tissue (n = 37)]. Effects of dual blockade of mTOR signaling using a rapamycin analogue (everolimus) and an epidermal/vascular endothelial growth factor receptor inhibitor (AEE788) were evaluated in liver cancer cell lines and in a xenograft model.

    Results: Aberrant mTOR signaling (p-RPS6) was present in half of the cases, associated with insulin-like growth factor pathway activation, epidermal growth factor up-regulation, and PTEN dysregulation. PTEN and PI3KCA-B mutations were rare events. Chromosomal gains in RICTOR (25% of patients) and positive p-RPS6 staining correlated with recurrence. RICTOR-specific siRNA down-regulation reduced tumor cell viability in vitro. Blockage of mTOR signaling with everolimus in vitro and in a xenograft model decelerated tumor growth and increased survival. This effect was enhanced in vivo after epidermal growth factor blockade.

    Conclusions: MTOR signaling has a critical role in the pathogenesis of HCC, with evidence for the role of RICTOR in hepato-oncogenesis. MTOR blockade with everolimus is effective in vivo. These findings establish a rationale for targeting the mTOR pathway in clinical trials in HCC.

    Funded by: NIDDK NIH HHS: 1R01DK076986-01, 1R01DK37340-23, R01 DK037340, R01 DK037340-22, R01 DK076986, R01 DK076986-01

    Gastroenterology 2008;135;6;1972-83, 1983.e1-11

Martin Del Castillo Velasco Herrera

- PhD Student

I obtained my Bachelor degree in Genome Sciences (Hons) from the National Autonomous University of Mexico in 2011. Prior to joining Sanger as a PhD Student, I participated in projects that focused in cancer gene discovery and high throughput sequencing data analysis.

Research

My PhD project focuses on the identification of genes involved in the metastatic process in melanoma. We use whole genome and transcriptome sequencing to identify potential candidate genes, followed by experimental validation using CRISPR-Cas9 experiments in-vitro and subsequently in-vivo murine models.

References

  • Off-target assessment of CRISPR-Cas9 guiding RNAs in human iPS and mouse ES cells.

    Tan EP, Li Y, Del Castillo Velasco-Herrera M, Yusa K and Bradley A

    Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.

    The CRISPR-Cas9 system consists of a site-specific, targetable DNA nuclease that holds great potential in gene editing and genome-wide screening applications. To apply the CRISPR-Cas9 system to these assays successfully, the rate at which Cas9 induces DNA breaks at undesired loci must be understood. We characterized the rate of Cas9 off-target activity in typical Cas9 experiments in two human and one mouse cell lines. We analyzed the Cas9 cutting activity of 12 gRNAs in both their targeted sites and ∼90 predicted off-target sites per gRNA. In a Cas9-based knockout experiment, gRNAs induced detectable Cas9 cutting activity in all on-target sites and in only a few off-target sites genome-wide in human 293FT, human-induced pluripotent stem (hiPS) cells, and mouse embryonic stem (ES) cells. Both the cutting rates and DNA repair patterns were highly correlated between the two human cell lines in both on-target and off-target sites. In clonal Cas9 cutting analysis in mouse ES cells, biallelic Cas9 cutting was observed with low off-target activity. Our results show that off-target activity of Cas9 is low and predictable by the degree of sequence identity between the gRNA and a potential off-target site. Off-target Cas9 activity can be minimized by selecting gRNAs with few off-target sites of near complementarity. genesis 53:225-236, 2015. © 2014 The Authors. Genesis Published by Wiley Periodicals, Inc.

    Genesis (New York, N.Y. : 2000) 2015;53;2;225-36

  • Telomere-Regulating Genes and the Telomere Interactome in Familial Cancers.

    Robles-Espinoza CD, Del Castillo Velasco-Herrera M, Hayward NK and Adams DJ

    Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom. cdre@sanger.ac.uk.

    Telomeres are repetitive sequence structures at the ends of linear chromosomes that consist of double-stranded DNA repeats followed by a short single-stranded DNA protrusion. Telomeres need to be replicated in each cell cycle and protected from DNA-processing enzymes, tasks that cells execute using specialized protein complexes such as telomerase (that includes TERT), which aids in telomere maintenance and replication, and the shelterin complex, which protects chromosome ends. These complexes are also able to interact with a variety of other proteins, referred to as the telomere interactome, to fulfill their biological functions and control signaling cascades originating from telomeres. Given their essential role in genomic maintenance and cell-cycle control, germline mutations in telomere-regulating proteins and their interacting partners have been found to underlie a variety of diseases and cancer-predisposition syndromes. These syndromes can be characterized by progressively shortening telomeres, in which carriers can present with organ failure due to stem cell senescence among other characteristics, or can also present with long or unprotected telomeres, providing an alternative route for cancer formation. This review summarizes the critical roles that telomere-regulating proteins play in cell-cycle control and cell fate and explores the current knowledge on different cancer-predisposing conditions that have been linked to germline defects in these proteins and their interacting partners. Mol Cancer Res; 13(2); 211-22. ©2014 AACR.

    Funded by: Cancer Research UK: 13031

    Molecular cancer research : MCR 2015;13;2;211-222

  • Genome-wide recessive genetic screening in mammalian cells with a lentiviral CRISPR-guide RNA library.

    Koike-Yusa H, Li Y, Tan EP, Velasco-Herrera Mdel C and Yusa K

    1] Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. [2].

    Identification of genes influencing a phenotype of interest is frequently achieved through genetic screening by RNA interference (RNAi) or knockouts. However, RNAi may only achieve partial depletion of gene activity, and knockout-based screens are difficult in diploid mammalian cells. Here we took advantage of the efficiency and high throughput of genome editing based on type II, clustered, regularly interspaced, short palindromic repeats (CRISPR)-CRISPR-associated (Cas) systems to introduce genome-wide targeted mutations in mouse embryonic stem cells (ESCs). We designed 87,897 guide RNAs (gRNAs) targeting 19,150 mouse protein-coding genes and used a lentiviral vector to express these gRNAs in ESCs that constitutively express Cas9. Screening the resulting ESC mutant libraries for resistance to either Clostridium septicum alpha-toxin or 6-thioguanine identified 27 known and 4 previously unknown genes implicated in these phenotypes. Our results demonstrate the potential for efficient loss-of-function screening using the CRISPR-Cas9 system.

    Funded by: Cancer Research UK; Wellcome Trust: WT077187

    Nature biotechnology 2014;32;3;267-73

  • Jdp2 downregulates Trp53 transcription to promote leukaemogenesis in the context of Trp53 heterozygosity.

    van der Weyden L, Rust AG, McIntyre RE, Robles-Espinoza CD, del Castillo Velasco-Herrera M, Strogantsev R, Ferguson-Smith AC, McCarthy S, Keane TM, Arends MJ and Adams DJ

    Wellcome Trust Sanger Institute, Cambridge, UK.

    We performed a genetic screen in mice to identify candidate genes that are associated with leukaemogenesis in the context of Trp53 heterozygosity. To do this we generated Trp53 heterozygous mice carrying the T2/Onc transposon and SB11 transposase alleles to allow transposon-mediated insertional mutagenesis to occur. From the resulting leukaemias/lymphomas that developed in these mice, we identified nine loci that are potentially associated with tumour formation in the context of Trp53 heterozygosity, including AB041803 and the Jun dimerization protein 2 (Jdp2). We show that Jdp2 transcriptionally regulates the Trp53 promoter, via an atypical AP-1 site, and that Jdp2 expression negatively regulates Trp53 expression levels. This study is the first to identify a genetic mechanism for tumour formation in the context of Trp53 heterozygosity.

    Funded by: Cancer Research UK: 13031, 14356; Medical Research Council: G0800024; Wellcome Trust: 095606

    Oncogene 2013;32;3;397-402

  • Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome.

    McIntyre RE, Lakshminarasimhan Chavali P, Ismail O, Carragher DM, Sanchez-Andrade G, Forment JV, Fu B, Del Castillo Velasco-Herrera M, Edwards A, van der Weyden L, Yang F, Sanger Mouse Genetics Project, Ramirez-Solis R, Estabel J, Gallagher FA, Logan DW, Arends MJ, Tsang SH, Mahajan VB, Scudamore CL, White JK, Jackson SP, Gergely F and Adams DJ

    Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.

    Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4), which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome. The mechanism by which disruption of CENPJ causes the proportionate, primordial growth failure that is characteristic of Seckel syndrome is unknown. By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpj(tm/tm)) that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus providing clear confirmation that specific mutations of CENPJ can cause Seckel syndrome. Immunohistochemistry revealed increased levels of DNA damage and apoptosis throughout Cenpj(tm/tm) embryos and adult mice showed an elevated frequency of micronucleus induction, suggesting that Cenpj-deficiency results in genomic instability. Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome. Instead, Cenpj(tm/tm) embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells. Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome.

    Funded by: Cancer Research UK: 11224, 12401, 13031, A11224; European Research Council: 268536; Medical Research Council: G0901338; NEI NIH HHS: K08 EY020530, NIH 1K08EY020530-01A1, R01 EY018213; Wellcome Trust: 092096, 098051

    PLoS genetics 2012;8;11;e1003022

Stefan Dentro

- PhD Student

Previously I've obtained a B.Sc. and M.Sc. in computer science, specialising in bioinformatics from Delft University of Technology in The Netherlands. For my masters thesis I've developed a classification approach that predicts the type of cancer through somatic point mutations.

Research

My project revolves around developing methods to construct the clonal architecture of tumours from sequencing data and applying these methods to available data sets. I'm part of ICGC-Pan-cancer where, together with the tumour heterogeneity and evolution working group, I work on uncovering the evolutionary story of 2500 tumours.

Richard Gunning

- PhD Student

BSc. Biochemistry at King's College London MSc. Bioinformatics at King's College London MRes. BBSRC DTP at Cambridge University

Research

Studying the Epigenetic regulation of Splicing in C57BL/6J mice

Marco Ranzani

- Postdoctoral Fellow

• July 2012- August 2013: Postdoctoral fellow at HSR-TIGET under the mentorship of Dr. E Montini. • January 2008-July 2012: Ph.D. student under the supervision of Dr. E Montini, Prof. L Naldini and Prof. M van Lohuizen. Ph.D. program in Cellular and Molecular Biology by San Raffaele Vita-Salute University, Milan, Italy and The Open University, London, UK. • September 2006-December 2007: Graduate fellow at HSR-TIGET under the supervision of Prof. L Naldini. • July 2006: MSc degree in Medical Biotechnology and Molecular Medicine. University of Milan, Italy. • July 2004: BSc in Medical Biotechnology. University of Milan, Italy.

Research

The aim of my project is to identify new therapies for the treatment of melanoma. I am characterizing the sensitivity to a library of anticancer drugs and drug combinations of a collection of melanoma cell lines. I will combine these results with mutations, copy number variations and gene expression of each cell line to identify markers of drug resistance. I will then utilized this knowledge to design new drug combinations for the efficient eradication of melanoma that will be validated in vitro and in vivo.

References

  • BRAF/NRAS wild-type melanoma, NF1 status and sensitivity to trametinib.

    Ranzani M, Alifrangis C, Perna D, Dutton-Regester K, Pritchard A, Wong K, Rashid M, Robles-Espinoza CD, Hayward NK, McDermott U, Garnett M and Adams DJ

    Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    Funded by: Cancer Research UK: 13031, 16629; Wellcome Trust: 102696

    Pigment cell & melanoma research 2015;28;1;117-9

  • Lentiviral vector-based insertional mutagenesis identifies genes involved in the resistance to targeted anticancer therapies.

    Ranzani M, Annunziato S, Calabria A, Brasca S, Benedicenti F, Gallina P, Naldini L and Montini E

    1] San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy [2] Current address: Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Cambridge, UK.

    The high transduction efficiency of lentiviral vectors in a wide variety of cells makes them an ideal tool for forward genetics screenings addressing issues of cancer research. Although molecular targeted therapies have provided significant advances in tumor treatment, relapses often occur by the expansion of tumor cell clones carrying mutations that confer resistance. Identification of the culprits of anticancer drug resistance is fundamental for the achievement of long-term response. Here, we developed a new lentiviral vector-based insertional mutagenesis screening to identify genes that confer resistance to clinically relevant targeted anticancer therapies. By applying this genome-wide approach to cell lines representing two subtypes of HER2(+) breast cancer, we identified 62 candidate lapatinib resistance genes. We validated the top ranking genes, i.e., PIK3CA and PIK3CB, by showing that their forced expression confers resistance to lapatinib in vitro and found that their mutation/overexpression is associated to poor prognosis in human breast tumors. Then, we successfully applied this approach to the identification of erlotinib resistance genes in pancreatic cancer, thus showing the intrinsic versatility of the approach. The acquired knowledge can help identifying combinations of targeted drugs to overcome the occurrence of resistance, thus opening new horizons for more effective treatment of tumors.

    Molecular therapy : the journal of the American Society of Gene Therapy 2014;22;12;2056-68

  • Cancer gene discovery goes mobile.

    van der Weyden L, Ranzani M and Adams DJ

    Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.

    A new study describes a tool, Lentihop, for somatic insertional mutagenesis in human cells and uses this system in combination with cancer genome data to define new genes and pathways involved in sarcoma development. Gene discovery in this way suggests that we are far from a complete catalog of cancer drivers.

    Funded by: Cancer Research UK: 13031

    Nature genetics 2014;46;9;928-9

  • Uncovering and dissecting the genotoxicity of self-inactivating lentiviral vectors in vivo.

    Cesana D, Ranzani M, Volpin M, Bartholomae C, Duros C, Artus A, Merella S, Benedicenti F, Sergi Sergi L, Sanvito F, Brombin C, Nonis A, Serio CD, Doglioni C, von Kalle C, Schmidt M, Cohen-Haguenauer O, Naldini L and Montini E

    San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.

    Self-inactivating (SIN) lentiviral vectors (LV) have an excellent therapeutic potential as demonstrated in preclinical studies and clinical trials. However, weaker mechanisms of insertional mutagenesis could still pose a significant risk in clinical applications. Taking advantage of novel in vivo genotoxicity assays, we tested a battery of LV constructs, including some with clinically relevant designs, and found that oncogene activation by promoter insertion is the most powerful mechanism of early vector-induced oncogenesis. SIN LVs disabled in their capacity to activate oncogenes by promoter insertion were less genotoxic and induced tumors by enhancer-mediated activation of oncogenes with efficiency that was proportional to the strength of the promoter used. On the other hand, when enhancer activity was reduced by using moderate promoters, oncogenesis by inactivation of tumor suppressor gene was revealed. This mechanism becomes predominant when the enhancer activity of the internal promoter is shielded by the presence of a synthetic chromatin insulator cassette. Our data provide both mechanistic insights and quantitative readouts of vector-mediated genotoxicity, allowing a relative ranking of different vectors according to these features, and inform current and future choices of vector design with increasing biosafety.

    Molecular therapy : the journal of the American Society of Gene Therapy 2014;22;4;774-85

  • One patient, two lesions, two oncogenic drivers of gastric cancer.

    Alsinet C, Ranzani M and Adams DJ

    Deep-sequencing of a primary tumor and metastasis from a single patient, and functional validation in culture, reveals that TGFBR2 and FGFR2 act as drivers of gastric cancer.

    Funded by: Cancer Research UK: 13031

    Genome biology 2014;15;8;444

  • Cancer gene discovery: exploiting insertional mutagenesis.

    Ranzani M, Annunziato S, Adams DJ and Montini E

    San Raffaele-Telethon Institute for Gene Therapy, via Olgettina 58, 20132, Milan, Italy. ranzani.marco@hsr.it.

    Insertional mutagenesis has been used as a functional forward genetics screen for the identification of novel genes involved in the pathogenesis of human cancers. Different insertional mutagens have been successfully used to reveal new cancer genes. For example, retroviruses are integrating viruses with the capacity to induce the deregulation of genes in the neighborhood of the insertion site. Retroviruses have been used for more than 30 years to identify cancer genes in the hematopoietic system and mammary gland. Similarly, another tool that has revolutionized cancer gene discovery is the cut-and-paste transposons. These DNA elements have been engineered to contain strong promoters and stop cassettes that may function to perturb gene expression upon integration proximal to genes. In addition, complex mouse models characterized by tissue-restricted activity of transposons have been developed to identify oncogenes and tumor suppressor genes that control the development of a wide range of solid tumor types, extending beyond those tissues accessible using retrovirus-based approaches. Most recently, lentiviral vectors have appeared on the scene for use in cancer gene screens. Lentiviral vectors are replication-defective integrating vectors that have the advantage of being able to infect nondividing cells, in a wide range of cell types and tissues. In this review, we describe the various insertional mutagens focusing on their advantages/limitations, and we discuss the new and promising tools that will improve the insertional mutagenesis screens of the future.

    Funded by: Cancer Research UK: 13031; Telethon: TGT11D01

    Molecular cancer research : MCR 2013;11;10;1141-58

  • Lentiviral vector-based insertional mutagenesis identifies genes associated with liver cancer.

    Ranzani M, Cesana D, Bartholomae CC, Sanvito F, Pala M, Benedicenti F, Gallina P, Sergi LS, Merella S, Bulfone A, Doglioni C, von Kalle C, Kim YJ, Schmidt M, Tonon G, Naldini L and Montini E

    San Raffaele-Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy.

    Transposons and γ-retroviruses have been efficiently used as insertional mutagens in different tissues to identify molecular culprits of cancer. However, these systems are characterized by recurring integrations that accumulate in tumor cells and that hamper the identification of early cancer-driving events among bystander and progression-related events. We developed an insertional mutagenesis platform based on lentiviral vectors (LVVs) by which we could efficiently induce hepatocellular carcinoma (HCC) in three different mouse models. By virtue of the LVV's replication-deficient nature and broad genome-wide integration pattern, LVV-based insertional mutagenesis allowed identification of four previously unknown liver cancer-associated genes from a limited number of integrations. We validated the oncogenic potential of all the identified genes in vivo, with different levels of penetrance. The newly identified genes are likely to play a role in human cancer because they are upregulated, amplified and/or deleted in human HCCs and can predict clinical outcomes of patients.

    Funded by: Telethon: TGT11D01

    Nature methods 2013;10;2;155-61

  • Notch1 regulates chemotaxis and proliferation by controlling the CC-chemokine receptors 5 and 9 in T cell acute lymphoblastic leukaemia.

    Mirandola L, Chiriva-Internati M, Montagna D, Locatelli F, Zecca M, Ranzani M, Basile A, Locati M, Cobos E, Kast WM, Asselta R, Paraboschi EM, Comi P and Chiaramonte R

    Department of Medicine, Surgery and Dentistry, Università degli Studi di Milano, Milan, Italy.

    Tumour cells often express deregulated profiles of chemokine receptors that regulate cancer cell migration and proliferation. Notch1 pathway activation is seen in T cell acute lymphoblastic leukaemia (T-ALL) due to the high frequency of Notch1 mutations affecting approximately 60% of patients, causing ligand-independent signalling and/or prolonging Notch1 half-life. We have investigated the possible regulative role of Notch1 on the expression and function of chemokine receptors CCR5, CCR9 and CXCR4 that play a role in determining blast malignant properties and localization of extramedullary infiltrations in leukaemia. We inhibited the pathway through γ-Secretase inhibitor and Notch1 RNA interference and analysed the effect on the expression and function of chemokine receptors. Our results indicate that γ-Secretase inhibitor negatively regulates the transcription level of the CC chemokine receptors 5 and 9 in T-ALL cell lines and patients' primary leukaemia cells, leaving CXCR4 expression unaltered. The Notch pathway also controls CCR5- and CCR9-mediated biological effects, ie chemotaxis and proliferation. Furthermore, engaging CCR9 through CCL25 administration rescues proliferation inhibition associated with abrogation of Notch activity. Finally, through RNA interference we demonstrated that the oncogenic isoform in T-ALL, Notch1, plays a role in controlling CCR5 and CCR9 expression and functions. These findings suggest that Notch1, acting in concert with chemokine receptors pathways, may provide leukaemia cells with proliferative advantage and specific chemotactic abilities, therefore influencing tumour cell progression and localization.

    The Journal of pathology 2012;226;5;713-22

  • Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection.

    Biffi A, Bartolomae CC, Cesana D, Cartier N, Aubourg P, Ranzani M, Cesani M, Benedicenti F, Plati T, Rubagotti E, Merella S, Capotondo A, Sgualdino J, Zanetti G, von Kalle C, Schmidt M, Naldini L and Montini E

    San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), via Olgettina 58, Milan, Italy.

    A recent clinical trial for adrenoleukodystrophy (ALD) showed the efficacy and safety of lentiviral vector (LV) gene transfer in hematopoietic stem progenitor cells. However, several common insertion sites (CIS) were found in patients' cells, suggesting that LV integrations conferred a selective advantage. We performed high-throughput LV integration site analysis on human hematopoietic stem progenitor cells engrafted in immunodeficient mice and found the same CISs reported in patients with ALD. Strikingly, most CISs in our experimental model and in patients with ALD cluster in megabase-wide chromosomal regions of high LV integration density. Conversely, cancer-triggering integrations at CISs found in tumor cells from γ-retroviral vector-based clinical trials and oncogene-tagging screenings in mice always target a single gene and are contained in narrow genomic intervals. These findings imply that LV CISs are produced by an integration bias toward specific genomic regions rather than by oncogenic selection.

    Funded by: Telethon: TGT11B01; Worldwide Cancer Research: 09-0676

    Blood 2011;117;20;5332-9

  • The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy.

    Montini E, Cesana D, Schmidt M, Sanvito F, Bartholomae CC, Ranzani M, Benedicenti F, Sergi LS, Ambrosi A, Ponzoni M, Doglioni C, Di Serio C, von Kalle C and Naldini L

    San Raffaele-Telethon Institute for Gene Therapy, via Olgettina 58, 20132 Milan, Italy. montini.eugenio@hsr.it

    gamma-Retroviral vectors (gammaRVs), which are commonly used in gene therapy, can trigger oncogenesis by insertional mutagenesis. Here, we have dissected the contribution of vector design and viral integration site selection (ISS) to oncogenesis using an in vivo genotoxicity assay based on transplantation of vector-transduced tumor-prone mouse hematopoietic stem/progenitor cells. By swapping genetic elements between gammaRV and lentiviral vectors (LVs), we have demonstrated that transcriptionally active long terminal repeats (LTRs) are major determinants of genotoxicity even when reconstituted in LVs and that self-inactivating (SIN) LTRs enhance the safety of gammaRVs. By comparing the genotoxicity of vectors with matched active LTRs, we were able to determine that substantially greater LV integration loads are required to approach the same oncogenic risk as gammaRVs. This difference in facilitating oncogenesis is likely to be explained by the observed preferential targeting of cancer genes by gammaRVs. This integration-site bias was intrinsic to gammaRVs, as it was also observed for SIN gammaRVs that lacked genotoxicity in our model. Our findings strongly support the use of SIN viral vector platforms and show that ISS can substantially modulate genotoxicity.

    Funded by: NHLBI NIH HHS: 2 P01 HL053750-11; Telethon: TGT06B01

    The Journal of clinical investigation 2009;119;4;964-75

Daniela Robles Espinoza

- Postdoctoral Fellow

I graduated with a Bachelor degree in Genome Sciences from the National Autonomous University of Mexico in 2009. I then worked for a year in two research groups focusing in cancer gene discovery and signaling networks, before joining the Sanger Institute as a PhD student.

Research

My PhD project and current work focus on the identification of novel melanoma susceptibility genes in predisposed families, and the mechanisms by which they might cause disease. We utilise whole- and targeted- exome sequencing and bioinformatic tools followed by the biological validation of targets in an effort to understand the genetics underlying this disease.

References

  • Nonsense mutations in the shelterin complex genes ACD and TERF2IP in familial melanoma.

    Aoude LG, Pritchard AL, Robles-Espinoza CD, Wadt K, Harland M, Choi J, Gartside M, Quesada V, Johansson P, Palmer JM, Ramsay AJ, Zhang X, Jones K, Symmons J, Holland EA, Schmid H, Bonazzi V, Woods S, Dutton-Regester K, Stark MS, Snowden H, van Doorn R, Montgomery GW, Martin NG, Keane TM, López-Otín C, Gerdes AM, Olsson H, Ingvar C, Borg A, Gruis NA, Trent JM, Jönsson G, Bishop DT, Mann GJ, Newton-Bishop JA, Brown KM, Adams DJ and Hayward NK

    Affiliations of authors: QIMR Berghofer Medical Research Institute, Brisbane, Australia (LGA, ALP, MG, PJ, JMP, JS, VB, SW, KDR, MSS, GWM, NGM, NKH); Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK (CDRE, TMK, DJA); Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark (KW, AMG); Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK (MH, HSn, DTB, JANB); Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (JC, KMB); Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA) Universidad de Oviedo, Oviedo, Spain (VQ, AJR, CLO); Cancer Genomics Research Laboratory, NCI Frederick, SAIC-Frederick Inc., Frederick MD (XZ, KJ); Department of Dermatology, Leiden University Medical Centre, Leiden, the Netherlands (RvD, NAG); Department of Clinical Sciences Lund, Division of Oncology and Pathology, Lund University, Lund, Sweden (HO, CI, ÅB, GJ); Translational Genomics Institute, Phoenix, AZ (JMT); University of Sydney at Westmead Millennium Institute, Westmead, Sydney, NSW, Australia (EAH, HSc, GJM); Melanoma Institute Australia, North Sydney, NSW, Australia (EAH, HSc, GJM).

    Background: The shelterin complex protects chromosomal ends by regulating how the telomerase complex interacts with telomeres. Following the recent finding in familial melanoma of inactivating germline mutations in POT1, encoding a member of the shelterin complex, we searched for mutations in the other five components of the shelterin complex in melanoma families.

    Methods: Next-generation sequencing techniques were used to screen 510 melanoma families (with unknown genetic etiology) and control cohorts for mutations in shelterin complex encoding genes: ACD, TERF2IP, TERF1, TERF2, and TINF 2. Maximum likelihood and LOD [logarithm (base 10) of odds] analyses were used. Mutation clustering was assessed with χ(2) and Fisher's exact tests. P values under .05 were considered statistically significant (one-tailed with Yates' correction).

    Results: Six families had mutations in ACD and four families carried TERF2IP variants, which included nonsense mutations in both genes (p.Q320X and p.R364X, respectively) and point mutations that cosegregated with melanoma. Of five distinct mutations in ACD, four clustered in the POT1 binding domain, including p.Q320X. This clustering of novel mutations in the POT1 binding domain of ACD was statistically higher (P = .005) in melanoma probands compared with population control individuals (n = 6785), as were all novel and rare variants in both ACD (P = .040) and TERF2IP (P = .022). Families carrying ACD and TERF2IP mutations were also enriched with other cancer types, suggesting that these variants also predispose to a broader spectrum of cancers than just melanoma. Novel mutations were also observed in TERF1, TERF2, and TINF2, but these were not convincingly associated with melanoma.

    Conclusions: Our findings add to the growing support for telomere dysregulation as a key process associated with melanoma susceptibility.

    Journal of the National Cancer Institute 2015;107;2

  • Telomere-Regulating Genes and the Telomere Interactome in Familial Cancers.

    Robles-Espinoza CD, Del Castillo Velasco-Herrera M, Hayward NK and Adams DJ

    Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom. cdre@sanger.ac.uk.

    Telomeres are repetitive sequence structures at the ends of linear chromosomes that consist of double-stranded DNA repeats followed by a short single-stranded DNA protrusion. Telomeres need to be replicated in each cell cycle and protected from DNA-processing enzymes, tasks that cells execute using specialized protein complexes such as telomerase (that includes TERT), which aids in telomere maintenance and replication, and the shelterin complex, which protects chromosome ends. These complexes are also able to interact with a variety of other proteins, referred to as the telomere interactome, to fulfill their biological functions and control signaling cascades originating from telomeres. Given their essential role in genomic maintenance and cell-cycle control, germline mutations in telomere-regulating proteins and their interacting partners have been found to underlie a variety of diseases and cancer-predisposition syndromes. These syndromes can be characterized by progressively shortening telomeres, in which carriers can present with organ failure due to stem cell senescence among other characteristics, or can also present with long or unprotected telomeres, providing an alternative route for cancer formation. This review summarizes the critical roles that telomere-regulating proteins play in cell-cycle control and cell fate and explores the current knowledge on different cancer-predisposing conditions that have been linked to germline defects in these proteins and their interacting partners. Mol Cancer Res; 13(2); 211-22. ©2014 AACR.

    Funded by: Cancer Research UK: 13031

    Molecular cancer research : MCR 2015;13;2;211-222

  • BRAF/NRAS wild-type melanoma, NF1 status and sensitivity to trametinib.

    Ranzani M, Alifrangis C, Perna D, Dutton-Regester K, Pritchard A, Wong K, Rashid M, Robles-Espinoza CD, Hayward NK, McDermott U, Garnett M and Adams DJ

    Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    Funded by: Cancer Research UK: 13031, 16629; Wellcome Trust: 102696

    Pigment cell & melanoma research 2015;28;1;117-9

  • POT1 loss-of-function variants predispose to familial melanoma.

    Robles-Espinoza CD, Harland M, Ramsay AJ, Aoude LG, Quesada V, Ding Z, Pooley KA, Pritchard AL, Tiffen JC, Petljak M, Palmer JM, Symmons J, Johansson P, Stark MS, Gartside MG, Snowden H, Montgomery GW, Martin NG, Liu JZ, Choi J, Makowski M, Brown KM, Dunning AM, Keane TM, López-Otín C, Gruis NA, Hayward NK, Bishop DT, Newton-Bishop JA and Adams DJ

    1] Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK. [2].

    Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.

    Funded by: Cancer Research UK: 10589, 13031, A10123, C1287/A9540, C588/A10589, C588/A4994, C8197/A10123; Wellcome Trust: WT091310, WT098051

    Nature genetics 2014;46;5;478-81

  • Cross-species analysis of mouse and human cancer genomes.

    Robles-Espinoza CD and Adams DJ

    Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1HH, United Kingdom.

    Fundamental advances in our understanding of the human cancer genome have been made over the last five years, driven largely by the development of next-generation sequencing (NGS) technologies. Here we will discuss the tools and technologies that have been used to profile human tumors, how they may be applied to the analysis of the mouse cancer genome, and the results thus far. In addition to mutations that disrupt cancer genes, NGS is also being applied to the analysis of the transcriptome of cancers, and, through the use of techniques such as ChIP-Seq, the protein-DNA landscape is also being revealed. Gaining a comprehensive picture of the mouse cancer genome, at the DNA level and through the analysis of the transcriptome and regulatory landscape, will allow us to "biofilter" for driver genes in more complex human cancers and represents a critical test to determine which mouse cancer models are faithful genetic surrogates of the human disease.

    Funded by: Cancer Research UK: 13031

    Cold Spring Harbor protocols 2014;2014;4;350-8

  • Cake: a bioinformatics pipeline for the integrated analysis of somatic variants in cancer genomes.

    Rashid M, Robles-Espinoza CD, Rust AG and Adams DJ

    Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, UK.

    We have developed Cake, a bioinformatics software pipeline that integrates four publicly available somatic variant-calling algorithms to identify single nucleotide variants with higher sensitivity and accuracy than any one algorithm alone. Cake can be run on a high-performance computer cluster or used as a stand-alone application. Availabilty: Cake is open-source and is available from http://cakesomatic.sourceforge.net/

    Funded by: Cancer Research UK: 13031; Wellcome Trust

    Bioinformatics (Oxford, England) 2013;29;17;2208-10

  • Jdp2 downregulates Trp53 transcription to promote leukaemogenesis in the context of Trp53 heterozygosity.

    van der Weyden L, Rust AG, McIntyre RE, Robles-Espinoza CD, del Castillo Velasco-Herrera M, Strogantsev R, Ferguson-Smith AC, McCarthy S, Keane TM, Arends MJ and Adams DJ

    Wellcome Trust Sanger Institute, Cambridge, UK.

    We performed a genetic screen in mice to identify candidate genes that are associated with leukaemogenesis in the context of Trp53 heterozygosity. To do this we generated Trp53 heterozygous mice carrying the T2/Onc transposon and SB11 transposase alleles to allow transposon-mediated insertional mutagenesis to occur. From the resulting leukaemias/lymphomas that developed in these mice, we identified nine loci that are potentially associated with tumour formation in the context of Trp53 heterozygosity, including AB041803 and the Jun dimerization protein 2 (Jdp2). We show that Jdp2 transcriptionally regulates the Trp53 promoter, via an atypical AP-1 site, and that Jdp2 expression negatively regulates Trp53 expression levels. This study is the first to identify a genetic mechanism for tumour formation in the context of Trp53 heterozygosity.

    Funded by: Cancer Research UK: 13031, 14356; Medical Research Council: G0800024; Wellcome Trust: 095606

    Oncogene 2013;32;3;397-402

Marcela Sjoberg

- Postdoctoral Fellow

I am a Molecular Biotechnology Engineer (2002), with a PhD degree in Molecular, Cellular Biology and Neuroscience (2006) from Universidad de Chile, Santiago, Chile. I did my postdoctoral training at the MRC Clinical Sciences Centre (Imperial College London, UK) examining mechanisms that control genome function in stem cells and immune cells during differentiation and cell cycle (2006-2010). Afterwards I acted as a consultant for the Chilean Stem Cell bank VidaCel®. In 2012 I joined the Sanger Institute as a Postdoctoral Fellow to develop a work package of the BLUEPRINT consortium project, aiming at generating epigenomic maps of blood cell types.

Research

Different cell types arise from the acquisition and maintenance of chemical modifications that modulate their genome function and define their epigenome. Cancer cells loose their identity and display significant alterations in their epigenome, however how genomic and epigenomic changes contribute to cancer development needs further examination. I am using strain-specific genome variation to uncover epigenome and gene expression changes in blood cells. By employing high-throughput sequencing technologies I have generated epigenomic (ChIP-seq and WGBS-oxWGBS) and transcriptomic (RNA-seq) profiles and we are currently cataloguing and quantifying genotype mediated epigenome variations, with a specific focus on DNA methylation and histone modifications.

References

  • An H3K9/S10 methyl-phospho switch modulates Polycomb and Pol II binding at repressed genes during differentiation.

    Sabbattini P, Sjoberg M, Nikic S, Frangini A, Holmqvist PH, Kunowska N, Carroll T, Brookes E, Arthur SJ, Pombo A and Dillon N

    Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom Genome Function Group, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom MRC Protein Phosphorylation Unit, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, United Kingdom.

    Methylated histones H3K9 and H3K27 are canonical epigenetic silencing modifications in metazoan organisms, but the relationship between the two modifications has not been well characterized. H3K9me3 coexists with H3K27me3 in pluripotent and differentiated cells. However, we find that the functioning of H3K9me3 is altered by H3S10 phosphorylation in differentiated postmitotic osteoblasts and cycling B cells. Deposition of H3K9me3/S10ph at silent genes is partially mediated by the mitogen- and stress-activated kinases (MSK1/2) and the Aurora B kinase. Acquisition of H3K9me3/S10ph during differentiation correlates with loss of paused S5 phosphorylated RNA polymerase II, which is present on Polycomb-regulated genes in embryonic stem cells. Reduction of the levels of H3K9me3/S10ph by kinase inhibition results in increased binding of RNAPIIS5ph and the H3K27 methyltransferase Ezh1 at silent promoters. Our results provide evidence of a novel developmentally regulated methyl-phospho switch that modulates Polycomb regulation in differentiated cells and stabilizes repressed states.

    Funded by: Medical Research Council: MC_U120061476

    Molecular biology of the cell 2014;25;6;904-15

  • The aurora B kinase and the polycomb protein ring1B combine to regulate active promoters in quiescent lymphocytes.

    Frangini A, Sjöberg M, Roman-Trufero M, Dharmalingam G, Haberle V, Bartke T, Lenhard B, Malumbres M, Vidal M and Dillon N

    Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Imperial College, Hammersmith Campus, London W12 0NN, UK.

    Reversible cellular quiescence is critical for developmental processes in metazoan organisms and is characterized by a reduction in cell size and transcriptional activity. We show that the Aurora B kinase and the polycomb protein Ring1B have essential roles in regulating transcriptionally active genes in quiescent lymphocytes. Ring1B and Aurora B bind to a wide range of active promoters in resting B and T cells. Conditional knockout of either protein results in reduced transcription and binding of RNA Pol II to promoter regions and decreased cell viability. Aurora B phosphorylates histone H3S28 at active promoters in resting B cells as well as inhibiting Ring1B-mediated ubiquitination of histone H2A and enhancing binding and activity of the USP16 deubiquitinase at transcribed genes. Our results identify a mechanism for regulating transcription in quiescent cells that has implications for epigenetic regulation of the choice between proliferation and quiescence.

    Funded by: Medical Research Council: MC_U120036884, MC_UP_1102/1, MC_UP_1102/2

    Molecular cell 2013;51;5;647-61

  • Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Abeta (25-35): involvement of lipid rafts.

    Hernandez P, Lee G, Sjoberg M and Maccioni RB

    Faculty of Sciences, Universidad de Chile, Santiago, Chile. cbb@uchile.cl

    Alzheimer's disease (AD) is characterized by the accumulation of protein filaments, namely extracellular amyloid-beta (Abeta) fibrils and intracellular neurofibrillary tangles, which are composed of aggregated hyperphosphorylated tau. Tau hyperphosphorylation is the product of deregulated Ser/Thr kinases such as cdk5 and GSK3beta. In addition, tau hyperphosphorylation also occurs at Tyr residues. To find a link between Abeta and tau phosphorylation, we investigated the effects of short-term Abeta treatments on SHSY-5Y cells. We analyzed phosphorylated tau variants in lipid rafts and the possible role of Tyr18 and Ser396/404 tau phosphorylation in Abeta-induced signaling cascades. After 2 min of Abeta treatment, phospho-Tyr18-tau and its association with rafts increased. Phospho-Ser 396/404-tau became detectable in rafts after 10 min treatment, which temporally correlated with the detection of cdk5 and p35 activator in lipid rafts. To determine the role of cdk5 in tau phosphorylation at Ser396/404 in lipid rafts, we pre-incubated cells with cdk5 inhibitor roscovitine, and observed that the Abeta-induced tau phosphorylation at Ser 396/404 in rafts was abolished as well as cdk5/p35 association with rafts. These data suggest a role for cdk5 in the Abeta-promoted early events involving tau hyperphosphorylation, and their possible implications for AD pathogenesis.

    Funded by: NINDS NIH HHS: NS32100

    Journal of Alzheimer's disease : JAD 2009;16;1;149-56

  • E180splice mutation in the growth hormone receptor gene in a Chilean family with growth hormone insensitivity: a probable common Mediterranean ancestor.

    Espinosa C, Sjoberg M, Salazar T, Rodriguez A, Cassorla FG, Mericq MV and Carvallo P

    Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile.

    Mutations in the GH receptor gene have been identified as the cause of growth hormone insensitivity syndrome (GHIS), a rare autosomal recessive disorder. We studied the clinical and biochemical characteristics and the coding sequence and intron-exon boundaries of the GH receptor gene in a consanguineous family with severe short stature which consisted of two patients, their parents and five siblings. The two adolescents had heights of -4.7 and -5.5 SDS, respectively, with elevated growth hormone associated with low IGF-I, IGFBP-3 and GHBP concentrations. Molecular analysis of the GH receptor gene revealed a mutation in exon 6, present in both patients This mutation, E180 splice, has been previously described in an Ecuadorian cohort, and in one Israeli and six Brazilian patients. We determined the GH receptor haplotypes based on six polymorphic sites in intron 9. Co-segregation of the E180splice mutation with haplotype I was found in this family, compatible with a common Mediterranean ancestor, as shown for previous cases with the E180splice mutation described to date.

    Journal of pediatric endocrinology & metabolism : JPEM 2008;21;12;1119-27

  • A novel role for the Aurora B kinase in epigenetic marking of silent chromatin in differentiated postmitotic cells.

    Sabbattini P, Canzonetta C, Sjoberg M, Nikic S, Georgiou A, Kemball-Cook G, Auner HW and Dillon N

    Gene Regulation and Chromatin Group, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, London, UK. pierangela.sabbattini@csc.mrc.ac.uk <pierangela.sabbattini@csc.mrc.ac.uk&gt;

    Combinatorial modifications of the core histones have the potential to fine-tune the epigenetic regulation of chromatin states. The Aurora B kinase is responsible for generating the double histone H3 modification tri-methylated K9/phosphorylated S10 (H3K9me3/S10ph), which has been implicated in chromosome condensation during mitosis. In this study, we have identified a novel role for Aurora B in epigenetic marking of silent chromatin during cell differentiation. We find that phosphorylation of H3 S10 by Aurora B generates high levels of the double H3K9me3/S10ph modification in differentiated postmitotic cells and also results in delocalisation of HP1beta away from heterochromatin in terminally differentiated plasma cells. Microarray analysis of the H3K9me3/S10ph modification shows a striking increase in the modification across repressed genes during differentiation of mesenchymal stem cells. Our results provide evidence that the Aurora B kinase has a role in marking silent chromatin independently of the cell cycle and suggest that targeting of Aurora B-mediated phosphorylation of H3 S10 to repressed genes could be a mechanism for epigenetic silencing of gene expression.

    Funded by: Medical Research Council: MC_U120036884

    The EMBO journal 2007;26;22;4657-69

  • Tau protein binds to pericentromeric DNA: a putative role for nuclear tau in nucleolar organization.

    Sjöberg MK, Shestakova E, Mansuroglu Z, Maccioni RB and Bonnefoy E

    Laboratory of Cellular, Molecular Biology and Neurosciences, Millennium Institute for Advanced Studies in Cell Biology and Biotechnology (CBB), Faculty of Sciences, University of Chile, Las Encinas 3370, Nuñoa, Santiago, Chile. cbb@uchile.cl

    The microtubule-associated tau protein participates in the organization and integrity of the neuronal cytoskeleton. A nuclear form of tau has been described in neuronal and non-neuronal cells, which displays a nucleolar localization during interphase but is associated with nucleolar-organizing regions in mitotic cells. In the present study, based on immunofluorescence, immuno-FISH and confocal microscopy, we show that nuclear tau is mainly present at the internal periphery of nucleoli, partially colocalizing with the nucleolar protein nucleolin and human AT-rich alpha-satellite DNA sequences organized as constitutive heterochromatin. By using gel retardation, we demonstrate that tau not only colocalizes with, but also specifically binds to, AT-rich satellite DNA sequences apparently through the recognition of AT-rich DNA stretches. Here we propose a functional role for nuclear tau in relation to the nucleolar organization and/or heterochromatinization of a portion of RNA genes. Since nuclear tau has also been found in neurons from patients with Alzheimer's disease (AD), aberrant nuclear tau could affect the nucleolar organization during the course of AD. We discuss nucleolar tau associated with AT-rich alpha-satellite DNA sequences as a potential molecular link between trisomy 21 and AD.

    Journal of cell science 2006;119;Pt 10;2025-34

  • Roles of cholesterol and lipids in the etiopathogenesis of Alzheimer's disease.

    Rojo L, Sjöberg MK, Hernández P, Zambrano C and Maccioni RB

    Laboratory of Cellular and Molecular Biology and Neurosciences, Millennium Institute for Advanced Studies in Cell Biology and Biotechnology (CBB), Nũñoa, Santiago, Chile.

    Alzheimer's disease is the principal cause of dementia throughout the world and the fourth cause of death in developed economies.This brain disorder is characterized by the formation of brain protein aggregates, namely, the paired helical filaments and senile plaques. Oxidative stress during life, neuroinflamamtion, and alterations in neuron-glia interaction patterns have been also involved in the etiopathogenesis of this disease. In recent years, cumulative evidence has been gained on the involvement of alteration in neuronal lipoproteins activity, as well as on the role of cholesterol and other lipids in the pathogenesis of this neurodegenerative disorder. In this review, we analyze the links between changes in cholesterol homeostasis, and the changes of lipids of major importance for neuronal activity and Alheimer's disease. The investigation on the fine molecular mechanisms underlying the lipids influence in the etiopathogenesis of Alzheimer's disease may shed light into its treatment and medical management.

    Journal of biomedicine & biotechnology 2006;2006;3;73976

  • Study of GH sensitivity in chilean patients with idiopathic short stature.

    Sjoberg M, Salazar T, Espinosa C, Dagnino A, Avila A, Eggers M, Cassorla F, Carvallo P and Mericq MV

    Institute of Maternal and Child Research (IDIMI), Faculty of Medicine, University of Chile, Santiago.

    We hypothesized that some children with idiopathic short stature in Chile might bear heterozygous mutations of the GH receptor. We selected 26 patients (3 females, 23 males) from 112 patients who consulted for idiopathic short stature at the University of Chile. Their chronological age was 8.3 +/- 1.9, and bone age was 6.1 +/- 1.0 yr. Their height was -3.0 +/- 0.7 SDS; IGF-I, -1.2 +/- 1.1 SD; IGF binding protein 3, -0.7 +/- 2.0 SDS; and GH binding protein, 0.4 +/- 0.8 SDS. Patients were admitted, and blood samples were obtained every 20 min to determine GH concentrations overnight. Coding sequences and intron-exon boundaries of exons 2-10 of GH receptor gene were amplified by PCR and subsequently analyzed through single-strand conformational analysis. Mean serum GH concentration, over 12-h, was 0.20 +/- 0.08 nM; pulse amplitude, 0.40 +/- 0.15 nM; number of peaks, 5.8 +/-1.5 peaks/12 h; peak value of GH during the 12-h sampling, 1.03 +/- 0.53 nM; and area under the curve, 151.4 +/- 56.1 nM/12 h. There were positive correlations between mean GH vs. area under the curve (P < 0.001) and GH peak (P < 0.01). The single-strand conformational analysis of the GH receptor gene showed abnormal migration for exon 6 in 9 patients and for exon 10 in 9 patients, which (by sequence analysis) corresponded to 2 polymorphisms of the GH receptor gene: an A-to-G transition in third position of codon 168 in exon 6 and a C-to-A transversion in the first position of codon 526 in exon 10. We further sequenced all coding exons and intron-exon boundaries in the most affected patients (nos. 6, 9, 11, 14, 15, 16, and 23). This analysis revealed a C-to-T transition in codon 161 of exon 6 in patient 23, which results in an amino acid change (Arg to Cys) in an heterozygous form in the patient and his father. In conclusion, the results of our study suggest that, in Chilean patients with idiopathic short stature, GH receptor gene mutations are uncommon, although we cannot exclude mutations that were missed by single-strand conformational analysis or mutations within introns or in the promoter regions of the GH receptor gene.

    The Journal of clinical endocrinology and metabolism 2001;86;9;4375-81

Louise Van Der Weyden

- Senior Staff Scientist

Dr. van der Weyden received her Ph.D. in cancer biology from the University of Sydney, Australia, before moving to the UK to work as a Post-doctoral Research Fellow at the WTSI. In Professor Allan Bradley’s laboratory her research focused on generating and characterising mouse models of cancer. This was further built on in Dr. David Adams’ laboratory where she used insertional mutagenesis (retroviruses and transposons) to identify genes that co-operate in tumorigenesis. Most recently, she has undertaken a research program that focuses on understanding the nature of metastasis, in particular melanoma metastasis.

Research

Most cancer patients die from metastasis rather than the primary tumour. This is what makes metastasis such an intriguing and important area of research. Melanoma is known for its intense metastatic propensity, so is a good model to study. I'm sequencing mouse melanoma cell lines with differing metastatic capacities and using cross-species comparison to identify which differentially expressed or mutated genes are also found in human datasets. I'm also performing an ‘experimental metastasis assay’ on KO mouse lines coming through the Mouse Genetics Program at the WTSI to identify mutants that show altered levels of pulmonary metastasis relative to controls.

References

  • Gray platelet syndrome: proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice.

    Guerrero JA, Bennett C, van der Weyden L, McKinney H, Chin M, Nurden P, McIntyre Z, Cambridge EL, Estabel J, Wardle-Jones H, Speak AO, Erber WN, Rendon A, Ouwehand WH and Ghevaert C

    Department of Haematology, University of Cambridge, and National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;

    NBEAL2 encodes a multidomain scaffolding protein with a putative role in granule ontogeny in human platelets. Mutations in NBEAL2 underlie gray platelet syndrome (GPS), a rare inherited bleeding disorder characterized by a lack of α-granules within blood platelets and progressive bone marrow fibrosis. We present here a novel Nbeal2(-/-) murine model of GPS and demonstrate that the lack of α-granules is due to their loss from platelets/mature megakaryocytes (MKs), and not by initial impaired formation. We show that the lack of Nbeal2 confers a proinflammatory phenotype to the bone marrow MKs, which in combination with the loss of proteins from α-granules drives the development of bone marrow fibrosis. In addition, we demonstrate that α-granule deficiency impairs platelet function beyond their purely hemostatic role and that Nbeal2 deficiency has a protective effect against cancer metastasis.

    Funded by: British Heart Foundation: FS09/039, RG/09/012/28096, RG/09/12/28096; Cancer Research UK: 13031; Department of Health: NF-SI-0510-10214; Wellcome Trust: WT098051

    Blood 2014;124;24;3624-35

  • Cancer gene discovery goes mobile.

    van der Weyden L, Ranzani M and Adams DJ

    Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.

    A new study describes a tool, Lentihop, for somatic insertional mutagenesis in human cells and uses this system in combination with cancer genome data to define new genes and pathways involved in sarcoma development. Gene discovery in this way suggests that we are far from a complete catalog of cancer drivers.

    Funded by: Cancer Research UK: 13031

    Nature genetics 2014;46;9;928-9

  • Insertional mutagenesis and deep profiling reveals gene hierarchies and a Myc/p53-dependent bottleneck in lymphomagenesis.

    Huser CA, Gilroy KL, de Ridder J, Kilbey A, Borland G, Mackay N, Jenkins A, Bell M, Herzyk P, van der Weyden L, Adams DJ, Rust AG, Cameron E and Neil JC

    Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, United Kingdom.

    Retroviral insertional mutagenesis (RIM) is a powerful tool for cancer genomics that was combined in this study with deep sequencing (RIM/DS) to facilitate a comprehensive analysis of lymphoma progression. Transgenic mice expressing two potent collaborating oncogenes in the germ line (CD2-MYC, -Runx2) develop rapid onset tumours that can be accelerated and rendered polyclonal by neonatal Moloney murine leukaemia virus (MoMLV) infection. RIM/DS analysis of 28 polyclonal lymphomas identified 771 common insertion sites (CISs) defining a 'progression network' that encompassed a remarkably large fraction of known MoMLV target genes, with further strong indications of oncogenic selection above the background of MoMLV integration preference. Progression driven by RIM was characterised as a Darwinian process of clonal competition engaging proliferation control networks downstream of cytokine and T-cell receptor signalling. Enhancer mode activation accounted for the most efficiently selected CIS target genes, including Ccr7 as the most prominent of a set of chemokine receptors driving paracrine growth stimulation and lymphoma dissemination. Another large target gene subset including candidate tumour suppressors was disrupted by intragenic insertions. A second RIM/DS screen comparing lymphomas of wild-type and parental transgenics showed that CD2-MYC tumours are virtually dependent on activation of Runx family genes in strong preference to other potent Myc collaborating genes (Gfi1, Notch1). Ikzf1 was identified as a novel collaborating gene for Runx2 and illustrated the interface between integration preference and oncogenic selection. Lymphoma target genes for MoMLV can be classified into (a) a small set of master regulators that confer self-renewal; overcoming p53 and other failsafe pathways and (b) a large group of progression genes that control autonomous proliferation in transformed cells. These findings provide insights into retroviral biology, human cancer genetics and the safety of vector-mediated gene therapy.

    Funded by: Cancer Research UK: 11951, 13031; Medical Research Council: G0801822

    PLoS genetics 2014;10;2;e1004167

  • Cancer of mice and men: old twists and new tails.

    van der Weyden L and Adams DJ

    Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK.

    In this review we set out to celebrate the contribution that mouse models of human cancer have made to our understanding of the fundamental mechanisms driving tumourigenesis. We take the opportunity to look forward to how the mouse will be used to model cancer and the tools and technologies that will be applied, and indulge in looking back at the key advances the mouse has made possible.

    Funded by: Cancer Research UK: 13031

    The Journal of pathology 2013;230;1;4-16

  • Jdp2 downregulates Trp53 transcription to promote leukaemogenesis in the context of Trp53 heterozygosity.

    van der Weyden L, Rust AG, McIntyre RE, Robles-Espinoza CD, del Castillo Velasco-Herrera M, Strogantsev R, Ferguson-Smith AC, McCarthy S, Keane TM, Arends MJ and Adams DJ

    Wellcome Trust Sanger Institute, Cambridge, UK.

    We performed a genetic screen in mice to identify candidate genes that are associated with leukaemogenesis in the context of Trp53 heterozygosity. To do this we generated Trp53 heterozygous mice carrying the T2/Onc transposon and SB11 transposase alleles to allow transposon-mediated insertional mutagenesis to occur. From the resulting leukaemias/lymphomas that developed in these mice, we identified nine loci that are potentially associated with tumour formation in the context of Trp53 heterozygosity, including AB041803 and the Jun dimerization protein 2 (Jdp2). We show that Jdp2 transcriptionally regulates the Trp53 promoter, via an atypical AP-1 site, and that Jdp2 expression negatively regulates Trp53 expression levels. This study is the first to identify a genetic mechanism for tumour formation in the context of Trp53 heterozygosity.

    Funded by: Cancer Research UK: 13031, 14356; Medical Research Council: G0800024; Wellcome Trust: 095606

    Oncogene 2013;32;3;397-402

  • Using mice to unveil the genetics of cancer resistance.

    van der Weyden L and Adams DJ

    Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. lvdw@sanger.ac.uk

    In the UK, four in ten people will develop some form of cancer during their lifetime, with an individual's relative risk depending on many factors, including age, lifestyle and genetic make-up. Much research has gone into identifying the genes that are mutated in tumorigenesis with the overwhelming majority of genetically-modified (GM) mice in cancer research showing accelerated tumorigenesis or recapitulating key aspects of the tumorigenic process. Yet if six out of ten people will not develop some form of cancer during their lifetime, together with the fact that some cancer patients experience spontaneous regression/remission, it suggests there are ways of 'resisting' cancer. Indeed, there are wildtype, spontaneously-arising mutants and GM mice that show some form of 'resistance' to cancer. Identification of mice with increased resistance to cancer is a novel aspect of cancer research that is important in terms of providing both chemopreventative and therapeutic options. In this review we describe the different mouse lines that display a 'cancer resistance' phenotype and discuss the molecular basis of their resistance.

    Funded by: Cancer Research UK: 13031; Wellcome Trust

    Biochimica et biophysica acta 2012;1826;2;312-30

  • Loss of RASSF1A synergizes with deregulated RUNX2 signaling in tumorigenesis.

    van der Weyden L, Papaspyropoulos A, Poulogiannis G, Rust AG, Rashid M, Adams DJ, Arends MJ and O'Neill E

    Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. lvdw@sanger.ac.uk

    The tumor suppressor gene RASSF1A is inactivated through point mutation or promoter hypermethylation in many human cancers. In this study, we conducted a Sleeping Beauty transposon-mediated insertional mutagenesis screen in Rassf1a-null mice to identify candidate genes that collaborate with loss of Rassf1a in tumorigenesis. We identified 10 genes, including the transcription factor Runx2, a transcriptional partner of Yes-associated protein (YAP1) that displays tumor suppressive activity through competing with the oncogenic TEA domain family of transcription factors (TEAD) for YAP1 association. While loss of RASSF1A promoted the formation of oncogenic YAP1-TEAD complexes, the combined loss of both RASSF1A and RUNX2 further increased YAP1-TEAD levels, showing that loss of RASSF1A, together with RUNX2, is consistent with the multistep model of tumorigenesis. Clinically, RUNX2 expression was frequently downregulated in various cancers, and reduced RUNX2 expression was associated with poor survival in patients with diffuse large B-cell or atypical Burkitt/Burkitt-like lymphomas. Interestingly, decreased expression levels of RASSF1 and RUNX2 were observed in both precursor T-cell acute lymphoblastic leukemia and colorectal cancer, further supporting the hypothesis that dual regulation of YAP1-TEAD promotes oncogenic activity. Together, our findings provide evidence that loss of RASSF1A expression switches YAP1 from a tumor suppressor to an oncogene through regulating its association with transcription factors, thereby suggesting a novel mechanism for RASSF1A-mediated tumor suppression.

    Funded by: Cancer Research UK: 13031, A6997, A9318, AI2932, C20510/A6997; Medical Research Council: 985361; Wellcome Trust: 082356

    Cancer research 2012;72;15;3817-27

  • Disruption of mouse Cenpj, a regulator of centriole biogenesis, phenocopies Seckel syndrome.

    McIntyre RE, Lakshminarasimhan Chavali P, Ismail O, Carragher DM, Sanchez-Andrade G, Forment JV, Fu B, Del Castillo Velasco-Herrera M, Edwards A, van der Weyden L, Yang F, Sanger Mouse Genetics Project, Ramirez-Solis R, Estabel J, Gallagher FA, Logan DW, Arends MJ, Tsang SH, Mahajan VB, Scudamore CL, White JK, Jackson SP, Gergely F and Adams DJ

    Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, United Kingdom.

    Disruption of the centromere protein J gene, CENPJ (CPAP, MCPH6, SCKL4), which is a highly conserved and ubiquitiously expressed centrosomal protein, has been associated with primary microcephaly and the microcephalic primordial dwarfism disorder Seckel syndrome. The mechanism by which disruption of CENPJ causes the proportionate, primordial growth failure that is characteristic of Seckel syndrome is unknown. By generating a hypomorphic allele of Cenpj, we have developed a mouse (Cenpj(tm/tm)) that recapitulates many of the clinical features of Seckel syndrome, including intrauterine dwarfism, microcephaly with memory impairment, ossification defects, and ocular and skeletal abnormalities, thus providing clear confirmation that specific mutations of CENPJ can cause Seckel syndrome. Immunohistochemistry revealed increased levels of DNA damage and apoptosis throughout Cenpj(tm/tm) embryos and adult mice showed an elevated frequency of micronucleus induction, suggesting that Cenpj-deficiency results in genomic instability. Notably, however, genomic instability was not the result of defective ATR-dependent DNA damage signaling, as is the case for the majority of genes associated with Seckel syndrome. Instead, Cenpj(tm/tm) embryonic fibroblasts exhibited irregular centriole and centrosome numbers and mono- and multipolar spindles, and many were near-tetraploid with numerical and structural chromosomal abnormalities when compared to passage-matched wild-type cells. Increased cell death due to mitotic failure during embryonic development is likely to contribute to the proportionate dwarfism that is associated with CENPJ-Seckel syndrome.

    Funded by: Cancer Research UK: 11224, 12401, 13031, A11224; European Research Council: 268536; Medical Research Council: G0901338; NEI NIH HHS: K08 EY020530, NIH 1K08EY020530-01A1, R01 EY018213; Wellcome Trust: 092096, 098051

    PLoS genetics 2012;8;11;e1003022

  • Increased tumorigenesis associated with loss of the tumor suppressor gene Cadm1.

    van der Weyden L, Arends MJ, Rust AG, Poulogiannis G, McIntyre RE and Adams DJ

    Experimental Cancer Genetics, The Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1HH, UK. lvdw@sanger.ac.uk

    Background: CADM1 encodes an immunoglobulin superfamily (IGSF) cell adhesion molecule. Inactivation of CADM1, either by promoter hypermethylation or loss of heterozygosity, has been reported in a wide variety of tumor types, thus it has been postulated as a tumor suppressor gene.

    Findings: We show for the first time that Cadm1 homozygous null mice die significantly faster than wildtype controls due to the spontaneous development of tumors at an earlier age and an increased tumor incidence of predominantly lymphomas, but also some solid tumors. Tumorigenesis was accelerated after irradiation of Cadm1 mice, with the reduced latency in tumor formation suggesting there are genes that collaborate with loss of Cadm1 in tumorigenesis. To identify these co-operating genetic events, we performed a Sleeping Beauty transposon-mediated insertional mutagenesis screen in Cadm1 mice, and identified several common insertion sites (CIS) found specifically on a Cadm1-null background (and not wildtype background).

    Conclusion: We confirm that Cadm1 is indeed a bona fide tumor suppressor gene and provide new insights into genetic partners that co-operate in tumorigenesis when Cadm1-expression is lost.

    Funded by: Cancer Research UK: 13031

    Molecular cancer 2012;11;29

  • Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis.

    March HN, Rust AG, Wright NA, ten Hoeve J, de Ridder J, Eldridge M, van der Weyden L, Berns A, Gadiot J, Uren A, Kemp R, Arends MJ, Wessels LF, Winton DJ and Adams DJ

    Cancer Research UK Cambridge Research Institute, Li Ka Shing Centre, UK.

    The evolution of colorectal cancer suggests the involvement of many genes. To identify new drivers of intestinal cancer, we performed insertional mutagenesis using the Sleeping Beauty transposon system in mice carrying germline or somatic Apc mutations. By analyzing common insertion sites (CISs) isolated from 446 tumors, we identified many hundreds of candidate cancer drivers. Comparison to human data sets suggested that 234 CIS-targeted genes are also dysregulated in human colorectal cancers. In addition, we found 183 CIS-containing genes that are candidate Wnt targets and showed that 20 CISs-containing genes are newly discovered modifiers of canonical Wnt signaling. We also identified mutations associated with a subset of tumors containing an expanded number of Paneth cells, a hallmark of deregulated Wnt signaling, and genes associated with more severe dysplasia included those encoding members of the FGF signaling cascade. Some 70 genes had co-occurrence of CIS pairs, clustering into 38 sub-networks that may regulate tumor development.

    Funded by: Cancer Research UK: 13031, A6997; Wellcome Trust

    Nature genetics 2011;43;12;1202-9

Chi Wong

- Postdoctoral Fellow

I am clinically trained haematologist with an interest in blood cell disorders. I undertook PhD training at the MRC Laboratory of Molecular Biology in Cambridge before joining the Sanger Institute.

Research

To understand the role of cancer gene aberrations discovered by genome sequencing efforts, I generate genetically tractable model systems to recapitulate these aberrations in vitro and in vivo. I study the phenotypic consequences of cancer-associated gene mutations using these models, which can also be used to investigate the underlying mechanisms underpinning the observed phenotypes. By understanding the mechanistic action of cancer-associated gene mutations, I hope to uncover new therapeutic strategies that can specifically target cellular pathways critical for cancer maintenence.

References

  • Inactivating CUX1 mutations promote tumorigenesis.

    Wong CC, Martincorena I, Rust AG, Rashid M, Alifrangis C, Alexandrov LB, Tiffen JC, Kober C, Chronic Myeloid Disorders Working Group of the International Cancer Genome Consortium, Green AR, Massie CE, Nangalia J, Lempidaki S, Döhner H, Döhner K, Bray SJ, McDermott U, Papaemmanuil E, Campbell PJ and Adams DJ

    1] Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. [2] Department of Haematology, University of Cambridge, Hills Road, Cambridge, UK.

    A major challenge in cancer genetics is to determine which low-frequency somatic mutations are drivers of tumorigenesis. Here we interrogate the genomes of 7,651 diverse human cancers and find inactivating mutations in the homeodomain transcription factor gene CUX1 (cut-like homeobox 1) in ~1-5% of various tumors. Meta-analysis of CUX1 mutational status in 2,519 cases of myeloid malignancies reveals disruptive mutations associated with poor survival, highlighting the clinical significance of CUX1 loss. In parallel, we validate CUX1 as a bona fide tumor suppressor using mouse transposon-mediated insertional mutagenesis and Drosophila cancer models. We demonstrate that CUX1 deficiency activates phosphoinositide 3-kinase (PI3K) signaling through direct transcriptional downregulation of the PI3K inhibitor PIK3IP1 (phosphoinositide-3-kinase interacting protein 1), leading to increased tumor growth and susceptibility to PI3K-AKT inhibition. Thus, our complementary approaches identify CUX1 as a pan-driver of tumorigenesis and uncover a potential strategy for treating CUX1-mutant tumors.

    Funded by: Cancer Research UK: 13031, 16629, A13031, A14356, A6542, A6997; Medical Research Council: G0800034; Wellcome Trust: 079249, 082356, 088340, 093867, 100140

    Nature genetics 2014;46;1;33-8

Robin van der Weide

- MSc. intern

Honours-student of the master "Cancer, Stem Cells and Developmental Biology" at Utrecht University. Interested in complex genetics and computational biology of vertebrate development and cancer. Previous work includes an internship in the group of Prof. Dr. Edwin Cuppen at the Hubrecht Institute.

Research

Studying predisposition for familial melanoma by functional annotation and analysis of SNPs from a large cohort.

* quick link - http://q.sanger.ac.uk/expcan