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

  • 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

    PUBMED: 18391979; DOI: 10.1038/onc.2008.94

  • 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

    PUBMED: 18485879; DOI: 10.1016/j.cell.2008.03.021; PMC: 2405818

  • 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

    PUBMED: 18505827; DOI: 10.1128/MCB.00272-08; PMC: 2493357

  • 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

    PUBMED: 17692468; DOI: 10.1016/j.bbcan.2007.06.003; PMC: 2586335

  • 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

    PUBMED: 16895910; DOI: 10.1074/jbc.M605720200

  • 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

    PUBMED: 16877353; PMC: 1698783

  • 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

    PUBMED: 16874317; DOI: 10.1038/ng0806-853a; PMC: 2610433

  • 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

    PUBMED: 16847348; DOI: 10.1101/gad.379706; PMC: 1522086

  • 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

    PUBMED: 16625196; DOI: 10.1038/nature04689; PMC: 2610434

  • 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

    PUBMED: 16611999; DOI: 10.1128/MCB.26.9.3595-3609.2006; PMC: 1447413