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

Nik-Zainal, Serena; Davies, Helen; Staaf, Johan LU ; Ramakrishna, Manasa; Glodzik, Dominik; Zou, Xueqing; Martincorena, Inigo; Alexandrov, Ludmil B; Martin, Sancha and Wedge, David C, et al. (2016) In Nature 534(7605). p.47-54
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... (More)

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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Breast Neoplasms, Cohort Studies, DNA Mutational Analysis, DNA Replication, DNA, Neoplasm, Female, Genes, BRCA1, Genes, BRCA2, Genome, Human, Genomics, Humans, Male, Mutagenesis, Mutation, Mutation Rate, Oncogenes, Recombinational DNA Repair
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Nature
volume
534
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7605
pages
8 pages
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Nature Publishing Group
external identifiers
  • Scopus:84973594792
ISSN
0028-0836
DOI
10.1038/nature17676
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English
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yes
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78b7cd41-aebe-4756-b732-c07ef1455952
date added to LUP
2016-08-16 12:03:44
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2016-11-20 04:35:07
@misc{78b7cd41-aebe-4756-b732-c07ef1455952,
  abstract     = {<p>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.</p>},
  author       = {Nik-Zainal, Serena and Davies, Helen and Staaf, Johan and Ramakrishna, Manasa and Glodzik, Dominik and Zou, Xueqing and Martincorena, Inigo and Alexandrov, Ludmil B and Martin, Sancha and Wedge, David C and Van Loo, Peter and Ju, Young Seok and Smid, Marcel and Brinkman, Arie B and Morganella, Sandro and Aure, Miriam R and Lingjærde, Ole Christian and Langerød, Anita and Ringnér, Markus and Ahn, Sung-Min and Boyault, Sandrine and Brock, Jane E and Broeks, Annegien and Butler, Adam and Desmedt, Christine and Dirix, Luc and Dronov, Serge and Fatima, Aquila and Foekens, John A and Gerstung, Moritz and Hooijer, Gerrit K J and Jang, Se Jin and Jones, David R and Kim, Hyung-Yong and King, Tari A and Krishnamurthy, Savitri and Lee, Hee Jin and Lee, Jeong-Yeon and Li, Yilong and McLaren, Stuart and Menzies, Andrew and Mustonen, Ville and O'Meara, Sarah and Pauporté, Iris and Pivot, Xavier and Purdie, Colin A and Raine, Keiran and Ramakrishnan, Kamna and Rodríguez-González, F Germán and Romieu, Gilles and Sieuwerts, Anieta M and Simpson, Peter T and Shepherd, Rebecca and Stebbings, Lucy and Stefansson, Olafur A and Teague, Jon and Tommasi, Stefania and Treilleux, Isabelle and Van den Eynden, Gert G and Vermeulen, Peter and Vincent-Salomon, Anne and Yates, Lucy and Caldas, Carlos and van't Veer, Laura and Tutt, Andrew and Knappskog, Stian and Tan, Benita Kiat Tee and Jonkers, Jos and Borg, Åke and Ueno, Naoto T and Sotiriou, Christos and Viari, Alain and Futreal, P Andrew and Campbell, Peter J and Span, Paul N and Van Laere, Steven and Lakhani, Sunil R and Eyfjord, Jorunn E and Thompson, Alastair M and Birney, Ewan and Stunnenberg, Hendrik G and van de Vijver, Marc J and Martens, John W M and Børresen-Dale, Anne-Lise and Richardson, Andrea L and Kong, Gu and Thomas, Gilles and Stratton, Michael R},
  issn         = {0028-0836},
  keyword      = {Breast Neoplasms,Cohort Studies,DNA Mutational Analysis,DNA Replication,DNA, Neoplasm,Female,Genes, BRCA1,Genes, BRCA2,Genome, Human,Genomics,Humans,Male,Mutagenesis,Mutation,Mutation Rate,Oncogenes,Recombinational DNA Repair},
  language     = {eng},
  month        = {06},
  number       = {7605},
  pages        = {47--54},
  publisher    = {ARRAY(0x9a4d078)},
  series       = {Nature},
  title        = {Landscape of somatic mutations in 560 breast cancer whole-genome sequences},
  url          = {http://dx.doi.org/10.1038/nature17676},
  volume       = {534},
  year         = {2016},
}