The identification of driver mutations and the cancer genes that they alter has been a central aim of cancer research for more than a quarter of a century. It has been a remarkably successful endeavour, with at least 350 (1.6%) of the ∼22,000 protein-coding genes in the human genome reported to show recurrent somatic mutations in cancer with strong evidence that these contribute to cancer development27 (http://www.sanger.ac.uk/genetics/CGP/Census/). Most were identified by first establishing their physical location in the genome through low-resolution genome-wide screens, in particular cytogenetics for chromosomal translocations in leukaemias and lymphomas. A few were discovered using biological assays for transforming activity of whole cancer cell DNA and others through targeted mutational screens guided by biologically well-informed guesswork. Mutations in ∼10% of these genes are also found in the germ line, where they confer an increased risk of developing cancer, and these were often initially identified by genetic linkage analysis of affected families. The size of the full repertoire of human cancer genes is a matter of speculation. However, studies in mice have suggested that more than 2,000 genes, when appropriately altered, may have the potential to contribute to cancer development28.

The known cancer genes run the gamut of tissue specificities and mutation prevalences. Some, for example TP53 and KRAS, are frequently mutated in diverse types of cancer whereas others are rare and/or restricted to one cancer type (http://www.sanger.ac.uk/genetics/CGP/cosmic/). In some cancer types, for example colorectal and pancreatic cancer, abnormalities in several known cancer genes are common. In contrast, in gastric cancer, relatively few mutations in known cancer genes have been reported.

Approximately 90% of the known somatically mutated cancer genes are dominantly acting, that is, mutation of just one allele is sufficient to contribute to cancer development. The mutation in such cases usually results in activation of the encoded protein. Ten per cent act in a recessive manner, requiring mutation of both alleles, and the mutations usually result in abrogation of protein function (these are sometimes known as tumour suppressor genes).

Patterns of mutation differ between dominant and recessive cancer genes. Recessive cancer genes are characterized by diverse mutation types, ranging from single base substitutions to whole gene deletions, which have the common outcome of abolishing the function of the encoded protein. In each dominantly acting cancer gene, however, the repertoire of cancer-causing somatic mutations is usually more constrained, both with respect to the type of mutation and its location in the gene. Missense amino acid changes (often restricted to certain key amino acids), in-frame insertions and deletions, and gene amplification are all common mutational mechanisms for activating dominantly acting cancer genes. Most, however, are activated through genomic rearrangement. This may join the sequences of two different genes to create a fusion gene or it may position the cancer gene adjacent to regulatory elements from elsewhere in the genome, resulting in abnormal expression patterns. Most of the known rearranged cancer genes are operative in the relatively rare subset of cancers constituted by leukaemias, lymphomas and sarcomas. Recently, however, rearranged cancer fusion genes were discovered in more than half of prostate cancer cases29 and in lung adenocarcinomas30. Their late discovery probably reflects the difficulty of identifying them amidst the jumble of passenger rearrangements present in many cancer genomes and hints that there are many more rearranged cancer genes to be found in common cancers.

Much of what we know about the biological pathways and processes that are subverted in cancer has originated from experiments exploring the functions of cancer genes. Certain gene families, notably the protein kinases, feature particularly prominently among cancer genes. Furthermore, cancer genes cluster on certain signalling pathways. For example, in the classical MAPK/ERK pathway31 upstream mutations are found in cell-membrane-bound receptor tyrosine kinases such as EGFR, ERBB2, FGFR1, FGFR2, FGFR3, PDGFRA and PDGFRB and also in the downstream cytoplasmic components NF1, PTPN11, HRAS, KRAS, NRAS and BRAF. Recent exhaustive mutational analyses in gliomas have indicated that almost all cases have a mutation at one of the genes on these critical signalling pathways32.

For some cancers, classification and treatment protocols are now defined by the presence of abnormal cancer genes. Acute myeloid leukaemia, for example, is subclassified on the basis of the presence of abnormalities involving specific cancer genes33. Each subtype has a characteristic gene expression profile, cellular morphology, clinical syndrome, prognosis and opportunity for targeted therapy. Moreover, because cancer cells are dependent on the abnormal proteins encoded by mutated cancer genes, they have become targets for the development of new cancer therapeutics. Flagships for this new generation of treatments include imatinib, an inhibitor of the proteins encoded by the ABL and KIT genes, which are mutated and activated, respectively, in chronic myeloid leukaemia34 and gastrointestinal stromal tumours35, and trastuzumab, an antibody directed against the protein encoded by ERBB2 (also known as HER2), which is commonly amplified and overexpressed in breast cancer36.