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Philip J Stephens,
Patrick S Tarpey,
Helen Davies,
Peter Van Loo,
Chris Greenman,
David C Wedge,
Serena Nik-Zainal,
Sancha Martin,
Ignacio Varela,
Graham R Bignell, [......],
Andrew Tutt,
Carlos Caldas,
Jorge S Reis-Filho,
Samuel A J R Aparicio,
Anne Vincent Salomon,
Anne-Lise Børresen-Dale,
Andrea L Richardson,
Peter J Campbell,
P Andrew Futreal,
Michael R Stratton
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ABSTRACT: All cancers carry somatic mutations in their genomes. A subset, known as driver mutations, confer clonal selective advantage on cancer cells and are causally implicated in oncogenesis, and the remainder are passenger mutations. The driver mutations and mutational processes operative in breast cancer have not yet been comprehensively explored. Here we examine the genomes of 100 tumours for somatic copy number changes and mutations in the coding exons of protein-coding genes. The number of somatic mutations varied markedly between individual tumours. We found strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade, and observed multiple mutational signatures, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides. Driver mutations were identified in several new cancer genes including AKT2, ARID1B, CASP8, CDKN1B, MAP3K1, MAP3K13, NCOR1, SMARCD1 and TBX3. Among the 100 tumours, we found driver mutations in at least 40 cancer genes and 73 different combinations of mutated cancer genes. The results highlight the substantial genetic diversity underlying this common disease.
Nature 06/2012; 486(7403):400-4. · 36.28 Impact Factor
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Ignacio Varela,
Patrick Tarpey,
Keiran Raine,
Dachuan Huang,
Choon Kiat Ong,
Philip Stephens,
Helen Davies,
David Jones,
Meng-Lay Lin,
Jon Teague, [......],
David J Adams,
Alistair Rust,
Waraporn Chan-On,
Chutima Subimerb,
Karl Dykema,
Kyle Furge,
Peter J Campbell,
Bin Tean Teh,
Michael R Stratton,
P Andrew Futreal
Nature 03/2012; · 36.28 Impact Factor
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Ignacio Varela,
Patrick Tarpey,
Keiran Raine,
Dachuan Huang,
Choon Kiat Ong,
Philip Stephens,
Helen Davies,
David Jones,
Meng-Lay Lin,
Jon Teague, [......],
David J Adams,
Alistair Rust,
Waraporn Chan-on,
Chutima Subimerb,
Karl Dykema,
Kyle Furge,
Peter J Campbell,
Bin Tean Teh,
Michael R Stratton,
P Andrew Futreal
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ABSTRACT: The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.
Nature 01/2011; 469(7331):539-42. · 36.28 Impact Factor
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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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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
[show abstract]
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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
