Patterns of somatic mutation in human cancer genomes

By Christopher Greenman, Philip J. Stephens, Raffaella Smith, G. Dalgliesh, C. Hunter, G. Bignell, Helen Davies, J. Teague, A. Butler, C. Stevens and 56 more. Nature, 2007

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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.

Subfields: Cancer Research, Genetics, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/8f24c071dfa0c2ed0e25e06610805aaf235b1983

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Citations in the corpus

Mutual exclusivity analysis identifies oncogenic network modules. (2012, background): “A key challenge in all of these projects is to distinguish ‘‘driver’’ mutations, which contribute to tumorigenesis, from ‘‘passenger’’ mutations, which are functionally neutral and do not contribute to tumor development (Greenman et al. 2007).”
KinMap: a web-based tool for interactive navigation through human kinome data (2017, background): “Due to their potential value in targeting oncogenesis [29], elucidating their 3D structures would provide a competitive advantage by guiding the rational development of novel inhibitors.”
Fibroblast growth factor signalling: from development to cancer (2010, background): “The importance of FGF signalling in tumour pathogenesis was highlighted by a screen of more than 1,000 somatic mutations found in the coding exons of 518 protein kinase genes from 210 different human cancer”
Living on a break: cellular senescence as a DNA-damage response (2008, background): “Mounting evidence points to DDR inactivation by genetic mutation of DDR genes in advanced cancers, and ATM is one of the protein kinase genes that most frequently carries driver mutations in human somatic cancer”
Universal Patterns of Selection in Cancer and Somatic Tissues (2018, neutral): “In early exome studies with small numbers of samples, methods to detect significant mutation recurrence at gene level often assumed that the substitution rate was uniform across genes (Bolli et al., 2014; Greenman et al., 2007; Lawrence et al., 2013).”
Cancer-specific High-throughput Annotation of Somatic Mutations: computational prediction of driver missense mutations (2009, background): “Projects to systematically resequence tumor genomes have discovered thousands of genes that were not previously linked to tumorigenesis but are somatically mutated in a relatively small fraction of tumors and may be important for tumor initiation or progression (1–6).”
Comprehensive Characterization of Cancer Driver Genes and Mutations (2018, background): “, 2016), the consequences of different mutations affecting the same gene (Torkamani and Schork, 2008), reliable tools for distinguishing driver mutations from passengers (Greenman et al., 2007), relationships between mutational signatures and driver genes (Alexandrov et al.”
Mutational Processes Molding the Genomes of 21 Breast Cancers (2012, background): “We have previously reported this signature in breast and other cancers (Greenman et al., 2007; Stephens et al., 2005, 2012).”