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Gillian L Dalgliesh,
Kyle Furge,
Chris Greenman,
Lina Chen,
Graham Bignell,
Adam Butler,
Helen Davies,
Sarah Edkins,
Claire Hardy,
Calli Latimer, [......],
Kelly Turrell,
Karl J Dykema,
Sok Kean Khoo,
David Petillo,
Bill Wondergem,
John Anema,
Richard J Kahnoski,
Bin Tean Teh,
Michael R Stratton,
P Andrew Futreal
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ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification-SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase-as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer.
Nature 01/2010; 463(7279):360-3. · 36.28 Impact Factor
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Patrick S Tarpey,
Raffaella Smith, Erin Pleasance,
Annabel Whibley,
Sarah Edkins,
Claire Hardy,
Sarah O'Meara,
Calli Latimer,
Ed Dicks,
Andrew Menzies, [......],
Michael Field,
Cindy Skinner,
Roger E Stevenson,
Martin Bobrow,
Gillian Turner,
Charles E Schwartz,
Jozef Gecz,
F Lucy Raymond,
P Andrew Futreal,
Michael R Stratton
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ABSTRACT: Large-scale systematic resequencing has been proposed as the key future strategy for the discovery of rare, disease-causing sequence variants across the spectrum of human complex disease. We have sequenced the coding exons of the X chromosome in 208 families with X-linked mental retardation (XLMR), the largest direct screen for constitutional disease-causing mutations thus far reported. The screen has discovered nine genes implicated in XLMR, including SYP, ZNF711 and CASK reported here, confirming the power of this strategy. The study has, however, also highlighted issues confronting whole-genome sequencing screens, including the observation that loss of function of 1% or more of X-chromosome genes is compatible with apparently normal existence.
Nature Genetics 05/2009; 41(5):535-43. · 35.53 Impact Factor
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Gijs van Haaften,
Gillian L Dalgliesh,
Helen Davies,
Lina Chen,
Graham Bignell,
Chris Greenman,
Sarah Edkins,
Claire Hardy,
Sarah O'Meara,
Jon Teague, [......],
Giovanni Tonon,
Ronald A DePinho,
Yu-Tzu Tai,
Kenneth C Anderson,
Richard J Kahnoski,
Aaron Massie,
Sok Kean Khoo,
Bin Tean Teh,
Michael R Stratton,
P Andrew Futreal
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ABSTRACT: Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene.
Nature Genetics 04/2009; 41(5):521-3. · 35.53 Impact Factor
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Graham R Bignell,
Thomas Santarius,
Jessica C M Pole,
Adam P Butler,
Janet Perry, Erin Pleasance,
Chris Greenman,
Andrew Menzies,
Sheila Taylor,
Sarah Edkins,
Peter Campbell,
Michael Quail,
Bob Plumb,
Lucy Matthews,
Kirsten McLay,
Paul A W Edwards,
Jane Rogers,
Richard Wooster,
P Andrew Futreal,
Michael R Stratton
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ABSTRACT: For decades, cytogenetic studies have demonstrated that somatically acquired structural rearrangements of the genome are a common feature of most classes of human cancer. However, the characteristics of these rearrangements at sequence-level resolution have thus far been subject to very limited description. One process that is dependent upon somatic genome rearrangement is gene amplification, a mechanism often exploited by cancer cells to increase copy number and hence expression of dominantly acting cancer genes. The mechanisms underlying gene amplification are complex but must involve chromosome breakage and rejoining. We sequenced 133 different genomic rearrangements identified within four cancer amplicons involving the frequently amplified cancer genes MYC, MYCN, and ERBB2. The observed architectures of rearrangement were diverse and highly distinctive, with evidence for sister chromatid breakage-fusion-bridge cycles, formation and reinsertion of double minutes, and the presence of bizarre clusters of small genomic fragments. There were characteristic features of sequences at the breakage-fusion junctions, indicating roles for nonhomologous end joining and homologous recombination-mediated repair mechanisms together with nontemplated DNA synthesis. Evidence was also found for sequence-dependent variation in susceptibility of the genome to somatic rearrangement. The results therefore provide insights into the DNA breakage and repair processes operative in somatic genome rearrangement and illustrate how the evolutionary histories of individual cancers can be reconstructed from large-scale cancer genome sequencing.
Genome Research 10/2007; 17(9):1296-303. · 13.61 Impact Factor
