Experimental cancer genetics

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

Their approach is to generate changes in the DNA sequence of mice (mutations) using a variety of techniques and to characterise the consequences of these sequence changes on cancer development. From this type of analysis, and in collaboration with several international research groups, the team is attempting to map cancer pathways, generating information that will be crucial for understanding the mechanisms of cancer formation in man. In addition, the team’s activities yield valuable genetic information on other important medical conditions such as infertility and fetal development.

The team is also involved in applying new-technology sequencing to decode the genomes of different mouse strains used widely in research laboratories throughout the world.

[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.

Research

Our aims

The Experimental cancer genetics team's primary interest is in identifying and characterising the genes involved in the development of cancer in the mouse, with a view to extending this knowledge to the understanding of cancer development in man.

Figure 1. Stained sections of tumour tissue from the Rassf1a knockout mice.

Figure 1. Stained sections of tumour tissue from the Rassf1a knockout mice.

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Our approach

Our approach is to mimic in the mouse the successive accumulation of genetic alterations (mutations) that are known to occur in the progression of human cancer.

We introduce a series of changes into mouse DNA using a technique called 'insertional mutagenesis'. The word 'mutagenesis' means 'generating mutations', and the 'insertional' part means that we do this by inserting small segments of DNA into the mouse genome. This process is random. The DNA insertion may disrupt a gene and render it non-functional, or it may function to activate gene expression.

This research is known as a forward genetic screen because we do not know in advance which genes will be mutated by the insertional mutagen so essentially we randomly mutate the genome and assess how these mutations influence cancer formation later on as the animal ages. By performing these studies on a large scale we hope to be able to map cancer pathways.

There are several technologies that we use for insertional mutagenesis in the mouse. These are based on using either retroviruses or a mobile genetic element called a 'transposon'. Transposons and viruses target different parts of the genome and therefore mutate different sets of genes. Transposons can be used in a range of tissues, while the use of viruses for insertional mutagenesis is largely restricted to the blood system and mammary gland.

We are particularly interested in studying a tumour suppressor gene called Rassf1a that we have shown to play a role in many different types of cancer, an observation that supports the belief that this gene is an important tumour suppressor gene in humans. We are also interested in cancers of the pancreas, bowel and breast.

While our focus is on the identification and characterisation of genes involved in cancer formation, some of the mouse models we have developed show up problems in areas not related to cancer. At present members of the group are characterising knockout mice that have problems related to infertility, foetal overgrowth and developmental defects.

Internal collaborations

We utilise the Sanger Institute's strengths in DNA sequencing and bioinformatics as part of our work. We also collaborate with the Genome informatics group; the Cancer genome project; the Vertebrate development and genetics group; and with the Mouse genomics group.

External collaborations

Some of these experiments have been performed in collaboration with Anton Bern, Jos Jonkers and Maarten van Lohuizen from the Netherlands Cancer Institute (NKI) in The Netherlands, Lara Collier and David Largaespada from the University of Minnesota, USA, and David Tuveson, Nikki March and Doug Winton at the Cambridge Cancer Research Institute.

Resource development projects

We are currently sequencing the genomes of several key mouse strains as part of the Mouse Genomes Project.

Training and collaboration

The research environment of the group offers opportunities for training and collaboration for individuals with an interest in mouse genetics, bioinformatics and cancer genetics. PhD students and post doctoral research scientists are encouraged to develop independent projects in an active and supportive research environment. PhD training positions are organised by the Sanger Institute PhD programme and candidates interested in post-doctoral and research assistant positions can contact the laboratory directly. Our laboratory has interactions with other groups in the Sanger Institute, in particular Ensembl; Sequencing; Informatics; Mouse genomics; and the Cancer genome project.

Grant support

The work of this team is supported by grants from The Wellcome Trust and Cancer Research UK.

Selected publications

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

Team

Team members

Daniela Robles Espinoza

- PhD Student

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 focuses on the identification of novel melanoma susceptibility genes in predisposed families. 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

  • 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; Wellcome Trust: 095606

    Oncogene 2013;32;3;397-402

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