Driver and Passenger Mutations in Cancer


Driver and Passenger Mutations in Cancer


Julia R. Pon and Marco A. Marra


Next-generation sequencing has allowed identification of millions of somatic mutations and epigenetic changes in cancer cells. A key challenge in interpreting cancer genomes and epigenomes is distinguishingwhich genetic and epigenetic changes are drivers of cancer development. Frequency-based and function-based approaches have been developed to identify candidate drivers; we discuss the advantages and drawbacks of these methods as well as their latest refinements.We focus particularly on identification of the types of drivers most likely to be missed, such as genes affected by copy number alterations, mutations in noncoding regions, dysregulation of microRNA, epigenetic changes, and mutations in chromatin modifiers.

< Key point>

***Similarities between driver mutations and driver epigenetic changes:
@Both are much less frequent than passengers.
@Some of each type are cancer type specific; some are not.
@Some of each type occur frequently; most occur rarely.
@Both may activate a gene in one cancer type and inactivate the same gene in a different cancer type.
@Both may be detected through effects on gene expression.
@Both may be identified by frequency-based approaches.
@Both may by produced by mechanisms related to environmental factors.
@Both require functional testing to confirm driver activity.
@Cancer cells may require drivers of either type for survival.
@Both tend to occur in a mutually exclusive manner with other drivers affecting the same allele.
@Both may be the “second hit” inactivating a tumor-suppressor gene.
@ Both may be acquired prior to cancer development.
@Both may affect alternative splicing.
@Both may directly or indirectly affect mutation rates and genome stability.

***Differences between driver mutations and driver epigenetic changes:
@The epigenome differs between cell types; the genome typically does not. Consequently, epigenetic changes detected in cancer versus normal samples are more likely than genetic changes to be false positives resulting from cell type differences.
@The process of culturing cells affects the epigenome much more than the genome. Cultured cells are thus less useful for cancer-specific epigenome change discovery than cancer-specific mutation discovery.
@Sites prone to epigenetic changes differ from sites prone to mutations; background frequency estimation thus differs.
@Epigenetic changes can be reversed more easily than genetic changes. Reversal of epigenetic changes can be used to reveal what impacts epigenetic changes had on gene expression.
@Genetic changes restricted to particular loci can be induced more easily than epigenetic changes restricted to particular loci, allowing easier investigation of the effects of a single genetic change than of a single epigenetic change.
@Driver epigenetic changes may tend to be acquired before driver mutations.
@Mutations may allow proteins to function in novel ways (i.e., have neomorphic activity), whereas epigenetic changes typically affect gene expression and so increase or decrease levels of normal activities (exceptions are discussed in the main text).


Annu. Rev. Pathol. Mech. Dis. 2015. 10:25–50

This article’s doi:10.1146/annurev-pathol-012414-040312