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Journal ArticleDOI

Patterns of somatic mutation in human cancer genomes

08 Mar 2007-Nature (Nature Publishing Group)-Vol. 446, Iss: 7132, pp 153-158
TL;DR: More than 1,000 somatic mutations found in 274 megabases of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers reveal the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
Abstract: Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.

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Journal ArticleDOI
Michael S. Lawrence1, Petar Stojanov2, Petar Stojanov1, Paz Polak3, Paz Polak1, Paz Polak2, Gregory V. Kryukov3, Gregory V. Kryukov2, Gregory V. Kryukov1, Kristian Cibulskis1, Andrey Sivachenko1, Scott L. Carter1, Chip Stewart1, Craig H. Mermel1, Craig H. Mermel2, Steven A. Roberts4, Adam Kiezun1, Peter S. Hammerman1, Peter S. Hammerman2, Aaron McKenna1, Aaron McKenna5, Yotam Drier, Lihua Zou1, Alex H. Ramos1, Trevor J. Pugh1, Trevor J. Pugh2, Nicolas Stransky1, Elena Helman6, Elena Helman1, Jaegil Kim1, Carrie Sougnez1, Lauren Ambrogio1, Elizabeth Nickerson1, Erica Shefler1, Maria L. Cortes1, Daniel Auclair1, Gordon Saksena1, Douglas Voet1, Michael S. Noble1, Daniel DiCara1, Pei Lin1, Lee Lichtenstein1, David I. Heiman1, Timothy Fennell1, Marcin Imielinski1, Marcin Imielinski2, Bryan Hernandez1, Eran Hodis1, Eran Hodis2, Sylvan C. Baca1, Sylvan C. Baca2, Austin M. Dulak1, Austin M. Dulak2, Jens G. Lohr2, Jens G. Lohr1, Dan A. Landau7, Dan A. Landau1, Dan A. Landau2, Catherine J. Wu2, Jorge Melendez-Zajgla, Alfredo Hidalgo-Miranda, Amnon Koren1, Amnon Koren2, Steven A. McCarroll2, Steven A. McCarroll1, Jaume Mora8, Ryan S. Lee2, Ryan S. Lee9, Brian D. Crompton2, Brian D. Crompton9, Robert C. Onofrio1, Melissa Parkin1, Wendy Winckler1, Kristin G. Ardlie1, Stacey Gabriel1, Charles W. M. Roberts2, Charles W. M. Roberts9, Jaclyn A. Biegel10, Kimberly Stegmaier1, Kimberly Stegmaier9, Kimberly Stegmaier2, Adam J. Bass1, Adam J. Bass2, Levi A. Garraway2, Levi A. Garraway1, Matthew Meyerson1, Matthew Meyerson2, Todd R. Golub, Dmitry A. Gordenin4, Shamil R. Sunyaev2, Shamil R. Sunyaev3, Shamil R. Sunyaev1, Eric S. Lander6, Eric S. Lander1, Eric S. Lander2, Gad Getz1, Gad Getz2 
11 Jul 2013-Nature
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.
Abstract: Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.

4,411 citations

Journal ArticleDOI
TL;DR: Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients.
Abstract: Methods We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition. Results A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months. Conclusions Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)

3,399 citations

Journal ArticleDOI
TL;DR: Analysis of genomic and clinical outcome data from 218 prostate cancer tumors revealed that copy-number alterations robustly define clusters of low- and high-risk disease beyond that achieved by Gleason score.

3,310 citations

Journal ArticleDOI
09 Apr 2009-Nature
TL;DR: This work has shown that the complete DNA sequence of large numbers of cancer genomes will be possible to obtain and will provide a detailed and comprehensive perspective on how individual cancers have developed.
Abstract: All cancers arise as a result of changes that have occurred in the DNA sequence of the genomes of cancer cells. Over the past quarter of a century much has been learnt about these mutations and the abnormal genes that operate in human cancers. We are now, however, moving into an era in which it will be possible to obtain the complete DNA sequence of large numbers of cancer genomes. These studies will provide us with a detailed and comprehensive perspective on how individual cancers have developed.

3,156 citations

Journal ArticleDOI
TL;DR: Genetic evidence suggests that tumour cells may also require specific interphase CDKs for proliferation, and selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.
Abstract: Tumour-associated cell cycle defects are often mediated by alterations in cyclin-dependent kinase (CDK) activity. Misregulated CDKs induce unscheduled proliferation as well as genomic and chromosomal instability. According to current models, mammalian CDKs are essential for driving each cell cycle phase, so therapeutic strategies that block CDK activity are unlikely to selectively target tumour cells. However, recent genetic evidence has revealed that, whereas CDK1 is required for the cell cycle, interphase CDKs are only essential for proliferation of specialized cells. Emerging evidence suggests that tumour cells may also require specific interphase CDKs for proliferation. Thus, selective CDK inhibition may provide therapeutic benefit against certain human neoplasias.

3,146 citations


Cites background from "Patterns of somatic mutation in hum..."

  • ...More recently, sequencing of human cancer genomes has revealed mutations in mitotic kinases such as aurora and Polo kinases, as well as in members of the Nek, Lats and Tlk familie...

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References
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Journal ArticleDOI
27 Jun 2002-Nature
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06 Dec 2002-Science
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7,486 citations

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TL;DR: This review focuses on the biochemical components and regulation of mammalian stress-regulated mitogen-activated protein kinase (MAPK) pathways, and the nuclear factor-kappa B pathway, a second stress signaling paradigm.
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PatentDOI
13 Aug 2007-Science
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.
Abstract: Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ˜90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention and monitoring.

3,152 citations

Journal ArticleDOI
TL;DR: A 'census' of cancer genes is conducted that indicates that mutations in more than 1% of genes contribute to human cancer.
Abstract: A central aim of cancer research has been to identify the mutated genes that are causally implicated in oncogenesis ('cancer genes'). After two decades of searching, how many have been identified and how do they compare to the complete gene set that has been revealed by the human genome sequence? We have conducted a 'census' of cancer genes that indicates that mutations in more than 1% of genes contribute to human cancer. The census illustrates striking features in the types of sequence alteration, cancer classes in which oncogenic mutations have been identified and protein domains that are encoded by cancer genes.

3,136 citations