Large scale screens for somatic mutations in human cancer genomes
All cancers are due to alterations in DNA. “Driver” mutations in cancer genes confer the neoplastic phenotype. Currently more than 350 genes in the human genome, when mutated, are known to contribute to oncogenesis. Cancers also carry “passenger” mutations that do not confer selective growth advantage. These occur any point in the cellular lineage from the first mitotic division of the fertilised egg to the progenitor of the last neoplastic clonal expansion. The number and pattern of passenger mutations in a cancer cell will be influenced by the number of mitoses in that lineage and by factors that alter the mutation rate, including exogenous exposures and defects in DNA maintenance. Large scale (ultimately genome-wide) systematic screens for somatic mutations in human cancer will yield both “driver” and “passenger” mutations. They therefore have the potential both to identify new cancer genes and to inform on the molecular evolution of each cancer. We have sequenced the coding exons of the family of 518 protein kinases, 1.3Mb DNA per cancer sample, in approximately 200 cancers of diverse histological types. Despite the screen being directed toward the coding regions of a gene family that is commonly implicated in oncogenesis, the results indicate that most somatic mutations detected are “passengers”. There is considerable variation in the number and pattern of these mutations between individual cancers, indicating substantial diversity of processes of molecular evolution between cancers. The imprints of exogenous mutagenic exposures, mutagenic treatment regimes and DNA repair defects can all be seen in the distinctive mutational signatures of individual cancers. This screen and others have yielded several frequently mutated cancer genes, for example BRAF, PIK3CA, and EGFR, which are now anticancer drug targets. However, detailed analyses of our data additionally suggest that there exist a substantial number of cancer genes that are infrequently mutated. Cells may be able to utilise mutations in a large repertoire of cancer genes to acquire the neoplastic phenotype. However, many of these genes are employed infrequently. These findings may have implications for future anticancer drug development.