Journal ArticleDOI
Diverse somatic mutation patterns and pathway alterations in human cancers
Zhengyan Kan,Bijay S. Jaiswal,Jeremy Stinson,Vasantharajan Janakiraman,Deepali Bhatt,Howard M. Stern,Peng Yue,Peter M. Haverty,Richard Bourgon,Jianbiao Zheng,Martin Moorhead,Subhra Chaudhuri,Lynn P. Tomsho,Brock A. Peters,Kanan Pujara,Shaun Cordes,David Davis,Victoria Carlton,Wenlin Yuan,Li Li,Weiru Wang,Charles Eigenbrot,Joshua S. Kaminker,David A. Eberhard,Paul Waring,Stephan C. Schuster,Zora Modrusan,Zemin Zhang,David Stokoe,Frederic J. de Sauvage,Malek Faham,Somasekar Seshagiri +31 more
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This study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.Abstract:
A large-scale genetic analysis of more than 400 breast, lung, ovarian and prostate cancer samples has identified thousands of cancer-related mutations. Kan et al. analysed DNA from cancer patients and identified 2,576 somatic mutations across 1,507 coding genes. Of these, 77 are thought to be significantly mutated, implying possible pathogenic roles for protein kinases, G protein-coupled receptors and other potential therapeutic targets. These authors performed a large-scale study in which they identified 2,576 somatic mutations across 1,507 coding genes from 441 breast, lung, ovarian and prostate cancer types and subtypes. The study provides an overview of the mutational spectra across major human cancers, implies an expanded role for Gα subunits in multiple cancer types and identifies several potential therapeutic targets. The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics1. Here we report the identification of 2,576 somatic mutations across ∼1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for gα subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Gα subunit) and mutant MAP2K4 (a member of the JNK signalling pathway) in oncogenesis. Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.read more
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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
Comprehensive genomic characterization of squamous cell lung cancers
Peter S. Hammerman,Doug Voet,Michael S. Lawrence,Douglas Voet,Rui Jing,Kristian Cibulskis,Andrey Sivachenko,Petar Stojanov,Aaron McKenna,Eric S. Lander,Eric S. Lander,Stacey Gabriel,Gad Getz,Marcin Imielinski,Elena Helman,Bryan Hernandez,Nam Pho,Matthew Meyerson,Andy Chu,Jung E. Hye-Chun,Andrew J. Mungall,Erin Pleasance,A. Gordon Robertson,Payal Sipahimalani,Dominik Stoll,Miruna Balasundaram,Inanc Birol,Yaron S.N. Butterfield,Eric Chuah,Robin J.N. Coope,Richard Corbett,Noreen Dhalla,Ranabir Guin,An He,Carrie Hirst,Martin Hirst,Robert A. Holt,Darlene Lee,Haiyan I. Li,Michael Mayo,Richard A. Moore,Karen Mungall,Ka Ming Nip,Adam B. Olshen,Jacqueline E. Schein,Jared R. Slobodan,Angela Tam,Nina Thiessen,Richard Varhol,Thomas Zeng,Yongjun Zhao,Steven J.M. Jones,Marco A. Marra,Gordon Saksena,Andrew D. Cherniack,Stephen E. Schumacher,Barbara Tabak,Scott L. Carter,Huy V. Nguyen,Robert C. Onofrio,Andrew Crenshaw,Kristin G. Ardlie,Rameen Beroukhim,Wendy Winckler,Alexei Protopopov,Alexei Protopopov,Jianhua Zhang,Jianhua Zhang,Angela Hadjipanayis,Semin Lee,Ruibin Xi,Lixing Yang,Xiaojia Ren,Hailei Zhang,Sachet A. Shukla,Peng Chieh Chen,Psalm Haseley,Eunjung Lee,Lynda Chin,Lynda Chin,Peter J. Park,Raju Kucherlapati,Nicholas D. Socci,Yupu Liang,Nikolaus Schultz,Laetitia Borsu,Alex E. Lash,Agnes Viale,Chris Sander,Marc Ladanyi,J. Todd Auman,Katherine A. Hoadley,Matthew D. Wilkerson,Yan Shi,Christina Liquori,Shaowu Meng,Ling Li,Yidi J. Turman,Michael D. Topal,Donghui Tan,Scot Waring,Elizabeth Buda,Jesse Walsh,Corbin D. Jones,Piotr A. Mieczkowski,Darshan Singh,Junyuan Wu,Anisha Gulabani,Peter Dolina,Tom Bodenheimer,Alan P. Hoyle,Janae V. Simons,Matthew G. Soloway,Joshua M. Stuart,Lisle E. Mose,Stuart R. Jefferys,Saianand Balu,Brian O'Connor,Derek Y. Chiang,Jinze Liu,Derek Y. Chiang,D. Neil Hayes,Charles M. Perou,Leslie Cope,Daniel J. Weisenberger,Ludmila Danilova,Daniel J. Weisenberger,Dennis T. 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Cabanski,Vonn Walter,James Stephen Marron,Yufeng Liu,Kai Wang,Jan F. Prins,Chad J. Creighton,Yiqun Zhang,William D. Travis,Natasha Rekhtman,Joanne Yi,Marie Christine Aubry,Richard T. Cheney,Sanja Dacic,Douglas B. Flieder,William K. Funkhouser,Peter B. Illei,Jerome Myers,Ming-Sound Tsao,Robert Penny,David Mallery,Troy Shelton,Martha Hatfield,Scott Morris,Peggy Yena,Candace Shelton,Mark Sherman,Joseph Paulauskis,Ramaswamy Govindan,Ijeoma Azodo,David G. Beer,Ron Bose,Lauren Averett Byers,David P. Carbone,Li-Wei Chang,Elizabeth Chun,Li Ding,John V. Heymach,Cristiane M. Ida,Bruce E. Johnson,Igor Jurisica,Jacob M. Kaufman,Farhad Kosari,David J. Kwiatkowski,Christopher G. Maher,William Pao,Martin Peifer,Martin Peifer,Gordon Robertson,Valerie W. Rusch,Jill M. Siegfried,Carrie Sougnez,Roman K. Thomas,Roman K. Thomas,Sandra C. Tomaszek,Charles J. Vaske,David A. Wheeler,Dennis A. Wigle,Christopher Wilks,Christopher Wilks,Jianjua John Zhang,Jianjua John Zhang,Mark A. Jensen,Robert Sfeir,Ari B. Kahn,Anna L. Chu,Prachi Kothiyal,Zhining Wang,Eric E. Snyder,Joan Pontius,Todd Pihl,Mark Backus,Jessica Walton,Julien Baboud,Dominique L. Berton,Matthew C. Nicholls,Deepak Srinivasan,Rohini Raman,Stanley Girshik,Peter A. Kigonya,Shelley Alonso,Rashmi N. Sanbhadti,Sean P. Barletta,John M. Greene,David Pot,Bizhan Bandarchi-Chamkhaleh,Jeff Boyd,JoEllen Weaver,Ijeoma A. Azodo,Sandra C. Tomaszek,Ping Yang,Malcolm V. Brock,Kristen Rogers,Marian Rutledge,Travis Brown,Beverly Lee,James Shin,Dante Trusty,Rajiv Dhir,Jill M. Siegfried,Olga Potapova,Konstantin V. Fedosenko,Maureen F. Zakowski,Elena Nemirovich-Danchenko,Mary Iacocca,Jennifer Brown,Brenda Rabeno,Christine Czerwinski,Nicholas J. Petrelli,Zhen Fan,Nicole Todaro,John Eckman,W. Kimryn Rathmell,Leigh B. Thorne,Mei Huang,Lori Boice,Ashley Hill,Erin Curley,Carl Morrison,Carmelo Gaudioso,John M. S. Bartlett,Sugy Kodeeswaran,Brent W. Zanke,Harman Sekhon,Kerstin David,Hartmut Juhl,Xuan Van Le,Bernard Kohl,Richard Thorp,Nguyen Viet Tien,Nguyen Van Bang,Howard H. Sussman,Bui Duc Phu,Richard A. Hajek,Nguyen Phi Hung,Khurram Z. Khan,Thomas Muley,Kenna R. Mills Shaw,Margi Sheth,Liming Yang,John A. Demchok,Tanja Davidsen,Kenneth H. Buetow,Greg Eley,Martin L. Ferguson,Laura A.L. Dillon,Carl F. Schaefer,Mark S. Guyer,Bradley A. Ozenberger,Jacqueline D. Palchik,Jane Peterson,Heidi J. Sofia,Elizabeth J. Thomson,Bruce E. Johnson,Ronglai Shen +345 more
TL;DR: It is shown that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour.
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.
Journal ArticleDOI
PhosphoSitePlus, 2014: mutations, PTMs and recalibrations
TL;DR: The ‘PTMVar’ dataset, an intersect of missense mutations and PTMs from PSP, identifies over 25 000 PTMVars (PTMs Impacted by Variants) that can rewire signaling pathways.
Journal ArticleDOI
A landscape of driver mutations in melanoma
Eran Hodis,Ian R. Watson,Ian R. Watson,Gregory V. Kryukov,Gregory V. Kryukov,Gregory V. Kryukov,Stefan T. Arold,Marcin Imielinski,Jean Philippe Theurillat,Elizabeth Nickerson,Daniel Auclair,Liren Li,Liren Li,Chelsea S. Place,Daniel DiCara,Alex H. Ramos,Alex H. Ramos,Michael S. Lawrence,Kristian Cibulskis,Andrey Sivachenko,Douglas Voet,Gordon Saksena,Nicolas Stransky,Robert C. Onofrio,Wendy Winckler,Kristin G. Ardlie,Nikhil Wagle,Nikhil Wagle,Jennifer A. Wargo,Kelly Chong,Donald L. Morton,Katherine Stemke-Hale,Guo Chen,Michael S. Noble,Matthew Meyerson,John E. Ladbury,Michael A. Davies,Jeffrey E. Gershenwald,Stephan N. Wagner,Dave S.B. Hoon,Dirk Schadendorf,Eric S. Lander,Eric S. Lander,Stacey Gabriel,Gad Getz,Levi A. Garraway,Lynda Chin +46 more
TL;DR: The spectrum of driver mutations provided unequivocal genomic evidence for a direct mutagenic role of UV light in melanoma pathogenesis, providing oncogenic insights in BRAF- and NRAS-driven melanoma as well as those without known NRAS/BRAF mutations.
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TL;DR: It is found that pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutations, which defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors.
PatentDOI
Consensus coding sequences of human breast and colorectal cancers
Tobias Sjöblom,Sian Jones,D. Williams Parsons,Laura D. Wood,Jimmy Lin,Thomas D. Barber,Diana Mandelker,Bert Vogelstein,Kenneth W. Kinzler,Victor E. Velculesu +9 more
TL;DR: In this paper, the authors analyzed 13,023 genes in 11 breast and 11 colorectal cancers and found that individual tumors accumulate an average of 90 mutant genes but only a subset of these contribute to the neoplastic process.
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A census of human cancer genes
P. Andrew Futreal,Lachlan J. M. Coin,Mhairi Marshall,Thomas A. Down,Tim Hubbard,Richard Wooster,Nazneen Rahman,Michael R. Stratton +7 more
TL;DR: A 'census' of cancer genes is conducted that indicates that mutations in more than 1% of genes contribute to human cancer.
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Comprehensive molecular portraits of human breast tumours
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Lawrence,Lihua Zou,Andrey Sivachenko,Pei Lin,Petar Stojanov,Rui Jing,Juok Cho,Raktim Sinha,Richard W. Park,Marc Danie Nazaire,James A. Robinson,Helga Thorvaldsdottir,Jill P. Mesirov,Peter J. Park,Sheila Reynolds,Richard Kreisberg,Brady Bernard,Ryan Bressler,Timo Erkkilä,Jake Lin,Vesteinn Thorsson,Wei Zhang,Ilya Shmulevich,Giovanni Ciriello,Nils Weinhold,Nikolaus Schultz,Jianjiong Gao,Ethan Cerami,Benjamin Gross,Anders Jacobsen,Rileen Sinha,B. Arman Aksoy,Yevgeniy Antipin,Boris Reva,Ronglai Shen,Barry S. Taylor,Marc Ladanyi,Chris Sander,Pavana Anur,Paul T. Spellman,Yiling Lu,Wenbin Liu,Roel R.G. Verhaak,Gordon B. Mills,Gordon B. Mills,Rehan Akbani,Nianxiang Zhang,Bradley M. Broom,Tod D. Casasent,Chris Wakefield,Anna K. Unruh,Keith A. Baggerly,Kevin R. Coombes,John N. Weinstein,David Haussler,Christopher C. Benz,Joshua M. Stuart,Stephen C. Benz,Jingchun Zhu,Christopher Szeto,Gary K. Scott,Christina Yau,Evan O. Paull,Daniel E. Carlin,Christopher K. Wong,Artem Sokolov,Janita Thusberg,Sean D. Mooney,Sam Ng,Theodore C. Goldstein,Kyle Ellrott,Mia Grifford,Christopher Wilks,Singer Ma,Brian Craft,Chunhua Yan,Ying Hu,Daoud Meerzaman,Julie M. Gastier-Foster,Julie M. Gastier-Foster,Jay Bowen,Nilsa C. Ramirez,Nilsa C. Ramirez,Aaron D. Black,Robert E. Pyatt,Robert E. Pyatt,Peter White,Peter White,Erik Zmuda,Jessica Frick,Tara M. Lichtenberg,Robin Brookens,Myra M. George,Mark Gerken,Hollie A. Harper,Kristen M. Leraas,Lisa Wise,Teresa R. Tabler,Cynthia McAllister,Thomas Barr,Melissa Hart-Kothari,Katie Tarvin,Charles Saller,George E. Sandusky,Colleen Mitchell,Mary Iacocca,Jennifer Brown,Brenda Rabeno,Christine Czerwinski,Nicholas J. Petrelli,Oleg Dolzhansky,Mikhail Abramov,Olga Voronina,Olga Potapova,Jeffrey R. Marks,Wiktoria Maria Suchorska,Dawid Murawa,Witold Kycler,Matthew Ibbs,Konstanty Korski,Arkadiusz Spychała,Pawel Murawa,Jacek J. Brzeziński,Hanna Perz,Radoslaw Łaźniak,M. 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