Box 1. Driver and passenger mutations

From the following article:

The cancer genome

Michael R. Stratton, Peter J. Campbell & P. Andrew Futreal

Nature 458, 719-724(9 April 2009)



All cancers arise as a result of somatically acquired changes in the DNA of cancer cells. That does not mean, however, that all the somatic abnormalities present in a cancer genome have been involved in development of the cancer. Indeed, it is likely that some have made no contribution at all. To embody this concept, the terms 'driver' and 'passenger' mutation have been coined.

A driver mutation is causally implicated in oncogenesis. It has conferred growth advantage on the cancer cell and has been positively selected in the microenvironment of the tissue in which the cancer arises. A driver mutation need not be required for maintenance of the final cancer (although it often is) but it must have been selected at some point along the lineage of cancer development shown in Fig. 1.

A passenger mutation has not been selected, has not conferred clonal growth advantage and has therefore not contributed to cancer development. Passenger mutations are found within cancer genomes because somatic mutations without functional consequences often occur during cell division. Thus, a cell that acquires a driver mutation will already have biologically inert somatic mutations within its genome. These will be carried along in the clonal expansion that follows and therefore will be present in all cells of the final cancer.

Some somatic mutations may actually impair cell survival. These will usually be subject to negative selection and hence be absent from the cancer genome. The traces of negative selection in cancer genomes are currently limited but it would be surprising if it was not operative.

A central goal of cancer genome analysis is the identification of cancer genes that, by definition, carry driver mutations. A key challenge will therefore be to distinguish driver from passenger mutations. The main strategy generally used exploits a number of structural signatures associated with mutations that are under positive selection. For example, driver mutations cluster in the subset of genes that are cancer genes whereas passenger mutations are more or less randomly distributed. This has been the approach adopted fruitfully in the past to identify most somatically mutated cancer genes in studies targeted at small regions of the genome.

Whole-genome sequencing, however, incorporating analysis of more than 20,000 protein-coding genes and unknown numbers of functional elements in intronic and intergenic DNA, presents a greater challenge, one rendered more daunting by the likelihood that passenger mutations in most cancer genomes substantially outnumber drivers. Because many cancer genes seem to contribute to cancer development in only a small fraction of tumours, large sample sets will have to be analysed to distinguish infrequently mutated cancer genes from genes with random clusters of passenger mutations. Furthermore, it is conceivable that some mutational processes are directed at specific genomic regions and thus generate clusters of passenger mutations that may be mistaken for drivers.

Therefore, all such signatures of positive selection need to be interpreted with caution. In practice, however, used in an informed and critical manner they will remain effective and reliable guides to the identification of cancer genes. Investigation of the biological consequences of putative driver mutations will often consolidate the evidence implicating them in oncogenesis and will provide insight into the subverted biological processes by which they contribute to cancer development.