The landscape of cancer genes and mutational processes in breast cancer
Philip J. Stephens,Patrick S. Tarpey,Helen Davies,Peter Van Loo,Peter Van Loo,Christopher Greenman,Christopher Greenman,David C. Wedge,Serena Nik-Zainal,Sancha Martin,Ignacio Varela,Graham R. Bignell,Lucy R. Yates,Lucy R. Yates,Elli Papaemmanuil,David Beare,Adam Butler,Angela Cheverton,John Gamble,Jonathan Hinton,Mingming Jia,Alagu Jayakumar,David Jones,Calli Latimer,King Wai Lau,Stuart McLaren,David J. McBride,Andrew Menzies,L. Mudie,Keiran Raine,Roland Rad,Michael Spencer Chapman,Jon W. Teague,Douglas F. Easton,Anita Langerød,Ming Ta Michael Lee,Chen-Yang Shen,Benita Tan Kiat Tee,Bernice Wong Huimin,Annegien Broeks,Ana Cristina Vargas,Gulisa Turashvili,John W.M. Martens,Aquila Fatima,Penelope Miron,Suet-Feung Chin,Gilles Thomas,Sandrine Boyault,Odette Mariani,Sunil R. Lakhani,Sunil R. Lakhani,Marc J. van de Vijver,Laura van 't Veer,John A. Foekens,Christine Desmedt,Christos Sotiriou,Andrew Tutt,Carlos Caldas,Carlos Caldas,Jorge S. Reis-Filho,Samuel Aparicio,Anne Vincent Salomon,Anne Lise Børresen-Dale,Anne Lise Børresen-Dale,Andrea L. Richardson,Peter J. Campbell,Peter J. Campbell,Peter J. Campbell,P. Andrew Futreal,Michael R. Stratton +69 more
TLDR
Strong correlations between mutation number, age at which cancer was diagnosed and cancer histological grade are found, and multiple mutational signatures are observed, including one present in about ten per cent of tumours characterized by numerous mutations of cytosine at TpC dinucleotides.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.read more
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Journal ArticleDOI
Signatures of mutational processes in human cancer
Ludmil B. Alexandrov,Serena Nik-Zainal,Serena Nik-Zainal,David C. Wedge,Samuel Aparicio,Sam Behjati,Sam Behjati,Andrew V. Biankin,Graham R. Bignell,Niccolo Bolli,Niccolo Bolli,Åke Borg,Anne Lise Børresen-Dale,Anne Lise Børresen-Dale,Sandrine Boyault,Birgit Burkhardt,Adam Butler,Carlos Caldas,Helen Davies,Christine Desmedt,Roland Eils,Jorunn E. Eyfjord,John A. Foekens,Mel Greaves,Fumie Hosoda,Barbara Hutter,Tomislav Ilicic,Sandrine Imbeaud,Sandrine Imbeaud,Marcin Imielinsk,Natalie Jäger,David T. W. Jones,David T. Jones,Stian Knappskog,Stian Knappskog,Marcel Kool,Sunil R. Lakhani,Carlos López-Otín,Sancha Martin,Nikhil C. Munshi,Nikhil C. Munshi,Hiromi Nakamura,Paul A. Northcott,Marina Pajic,Elli Papaemmanuil,Angelo Paradiso,John V. Pearson,Xose S. Puente,Keiran Raine,Manasa Ramakrishna,Andrea L. Richardson,Andrea L. Richardson,Julia Richter,Philip Rosenstiel,Matthias Schlesner,Ton N. Schumacher,Paul N. Span,Jon W. Teague,Yasushi Totoki,Andrew Tutt,Rafael Valdés-Mas,Marit M. van Buuren,Laura van ’t Veer,Anne Vincent-Salomon,Nicola Waddell,Lucy R. Yates,Icgc PedBrain,Jessica Zucman-Rossi,Jessica Zucman-Rossi,P. Andrew Futreal,Ultan McDermott,Peter Lichter,Matthew Meyerson,Matthew Meyerson,Sean M. Grimmond,Reiner Siebert,Elias Campo,Tatsuhiro Shibata,Stefan M. Pfister,Stefan M. Pfister,Peter J. Campbell,Peter J. Campbell,Peter J. Campbell,Michael R. Stratton,Michael R. Stratton +84 more
TL;DR: It is shown that hypermutation localized to small genomic regions, ‘kataegis’, is found in many cancer types, and this results reveal the diversity of mutational processes underlying the development of cancer.
Journal ArticleDOI
Cancer Genome Landscapes
Bert Vogelstein,Nickolas Papadopoulos,Victor E. Velculescu,Shibin Zhou,Luis A. Diaz,Kenneth W. Kinzler +5 more
TL;DR: This work has revealed the genomic landscapes of common forms of human cancer, which consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of "hills" (Genes altered infrequently).
Journal ArticleDOI
Mutational heterogeneity in cancer and the search for new cancer-associated genes
Michael S. Lawrence,Petar Stojanov,Petar Stojanov,Paz Polak,Paz Polak,Paz Polak,Gregory V. Kryukov,Gregory V. Kryukov,Gregory V. Kryukov,Kristian Cibulskis,Andrey Sivachenko,Scott L. Carter,Chip Stewart,Craig H. Mermel,Craig H. Mermel,Steven A. Roberts,Adam Kiezun,Peter S. Hammerman,Peter S. Hammerman,Aaron McKenna,Aaron McKenna,Yotam Drier,Lihua Zou,Alex H. Ramos,Trevor J. Pugh,Trevor J. Pugh,Nicolas Stransky,Elena Helman,Elena Helman,Jaegil Kim,Carrie Sougnez,Lauren Ambrogio,Elizabeth Nickerson,Erica Shefler,Maria L. Cortes,Daniel Auclair,Gordon Saksena,Douglas Voet,Michael S. Noble,Daniel DiCara,Pei Lin,Lee Lichtenstein,David I. Heiman,Timothy Fennell,Marcin Imielinski,Marcin Imielinski,Bryan Hernandez,Eran Hodis,Eran Hodis,Sylvan C. Baca,Sylvan C. Baca,Austin M. Dulak,Austin M. Dulak,Jens G. Lohr,Jens G. Lohr,Dan A. Landau,Dan A. Landau,Dan A. Landau,Catherine J. Wu,Jorge Melendez-Zajgla,Alfredo Hidalgo-Miranda,Amnon Koren,Amnon Koren,Steven A. McCarroll,Steven A. McCarroll,Jaume Mora,Ryan S. Lee,Ryan S. Lee,Brian D. Crompton,Brian D. Crompton,Robert C. Onofrio,Melissa Parkin,Wendy Winckler,Kristin G. Ardlie,Stacey Gabriel,Charles W. M. Roberts,Charles W. M. Roberts,Jaclyn A. Biegel,Kimberly Stegmaier,Kimberly Stegmaier,Kimberly Stegmaier,Adam J. Bass,Adam J. Bass,Levi A. Garraway,Levi A. Garraway,Matthew Meyerson,Matthew Meyerson,Todd R. Golub,Dmitry A. Gordenin,Shamil R. Sunyaev,Shamil R. Sunyaev,Shamil R. Sunyaev,Eric S. Lander,Eric S. Lander,Eric S. Lander,Gad Getz,Gad Getz +96 more
TL;DR: A fundamental problem with cancer genome studies is described: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds and the list includes many implausible genes, suggesting extensive false-positive findings that overshadow true driver events.
Journal ArticleDOI
Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage
Alexis C. Komor,Yongjoo Kim,Yongjoo Kim,Michael S. Packer,Michael S. Packer,John A. Zuris,John A. Zuris,David R. Liu,David R. Liu +8 more
TL;DR: E engineered fusions of CRISPR/Cas9 and a cytidine deaminase enzyme that retain the ability to be programmed with a guide RNA, do not induce dsDNA breaks, and mediate the direct conversion of cytidine to uridine, thereby effecting a C→T (or G→A) substitution.
Journal Article
Patterns of Somatic Mutation in Human Cancer Genomes
TL;DR: In this paper, the coding exons of the family of 518 protein kinases were sequenced in 210 cancers of diverse histological types to explore the nature of the information that will be derived from cancer genome sequencing.
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