Patterns of somatic mutation in human cancer genomes

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. Over 350 cancer-causing genes have been identified by established techniques such as mapping, bioassay and by identifying plausible biological candidates. The availability of the human genome sequence now means that large-scale sequencing studies can uncover many more candidate cancer genes. Protein kinase enzymes are key to many regulatory processes and their dysfunction is a common trigger for tumours. So a sample of 518 kinases associated with more than 200 different cancers was chosen for a major sequencing effort. The study reveals more than 1, 000 previously unknown mutations linked to tumour formation — some as 'passengers' that don't contribute to cancer formation, but over 100 of them as 'driver' mutations that do contribute to disease development. As well as revealing cancer-causing defects, gene family studies like this can uncover new targets for molecular diagnostics and therapeutics. 518 protein kinase genes in the human genome have been sequenced in a large sample of tumours, providing a global view of the patterns of mutations found and the variations in the number and type of mutations between individual tumours.