Landscape of somatic mutations in 560 breast cancer whole-genome sequences

Serena Nik-Zainal 1 Helen R. Davies 1 Johan Staaf 2 Manasa Ramakrishna 1 Dominik Glodzik 1 Xueqing Zou 1 Inigo Martincorena 1 Ludmil B. Alexandrov 1 Sancha Martin 1 David C. Wedge 1 Peter van Loo 1 Young Seok Ju 1 Marcel Smid 3 Arie B. Brinkman 4 Sandro Morganella 1 Miriam R. Aure 5 Ole Christian Lingjærde 6 Anita Langerød 5 Markus Ringnér 2 Sung-Min Ahn 7 Sandrine Boyault 8 Jane E. Brock 9 Anne Broeks 10 Adam Butler 1 Christine Desmedt 11 Luc Dirix 12 Serge Dronov 1 Aquila Fatima 13 John A. Foekens 3 Moritz Gerstung 1 Gerrit K. J. Hooijer 14 Se Jin Jang 15 David R. Jones 16, 1 Hyung-Yong Kim 17 Tari A. King 18 Savitri Krishnamurthy 19 Hee Jin Lee 15 Jeong-Yeon Lee 20 Yilong Li 1 Stuart Mclaren 1 Andrew Menzies 1 Ville Mustonen 1 Sarah O’meara 1 Iris Pauporté 21 Xavier Pivot 22 Colin A. Purdie 23 Keiran Raine 1 Kamna Ramakrishnan 1 F. Germán Rodríguez-González 3, 24, 25 Gilles Romieu 26 Anieta M. Sieuwerts 27, 28 Peter Simpson 29 Rebecca Shepherd 1 Lucy Stebbings 1 Olafur A. Stefansson 30 Jon Teague 1 Stefania Tommasi 31 Isabelle Treilleux 32 Gert G. van den Eynden 33 Peter Vermeulen 34 Anne Vincent-Salomon 35, 36 Lucy Yates 1 Carlos Caldas 37 Laura Van’t Veer 38, 39 Andrew Tutt 40 Stian Knappskog 41 Benita Kiat Tee Tan 42 Jos Jonkers 43 Åke Borg 2 Naoto T. Ueno 44, 45 Christos Sotiriou 46 Alain Viari 47, 48 P. Andrew Futreal 1 Peter J. Campbell 1 Paul N. Span 49, 50 Steven van Laere 51, 52 Sunil R. Lakhani 29 Jorunn E. Eyfjord 30 Alastair M. Thompson 53 Ewan Birney 1 Hendrik G. Stunnenberg 54 Marc J. van de Vijver 14 John W. M. Martens 3 Anne-Lise Børresen-Dale 5 Andrea L. Richardson 55 Gu Kong 56 Gilles Thomas 57 Michael R. Stratton 1
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Abstract : We analysed whole-genome sequences of 560 breast cancers to advance understanding of the driver mutations conferring clonal advantage and the mutational processes generating somatic mutations. We found that 93 protein-coding cancer genes carried probable driver mutations. Some non-coding regions exhibited high mutation frequencies, but most have distinctive structural features probably causing elevated mutation rates and do not contain driver mutations. Mutational signature analysis was extended to genome rearrangements and revealed twelve base substitution and six rearrangement signatures. Three rearrangement signatures, characterized by tandem duplications or deletions, appear associated with defective homologous-recombination-based DNA repair: one with deficient BRCA1 function, another with deficient BRCA1 or BRCA2 function, the cause of the third is unknown. This analysis of all classes of somatic mutation across exons, introns and intergenic regions highlights the repertoire of cancer genes and mutational processes operating, and progresses towards a comprehensive account of the somatic genetic basis of breast cancer.
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Serena Nik-Zainal, Helen R. Davies, Johan Staaf, Manasa Ramakrishna, Dominik Glodzik, et al.. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature, Nature Publishing Group, 2016, 534 (7605), pp.47 - 54. ⟨10.1038/nature17676⟩. ⟨hal-01388447⟩

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