Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer

http://elifesciences.org/content/3/e02935

Young Seok Ju, Ludmil B Alexandrov, Moritz Gerstung et al.

Mitochondrial DNA (mtDNA) mutations are often observed in cancer, but their causal significance in tumorigenesis has been called into question. This study extensively explores somatic mtDNA mutation in 1675 tumours, and compare their findings to a null model of random genetic drift. They find that silent/missense mutations occur at a rate predicted by simulations of random genetic drift, due to endogenous copying errors during mtDNA replication. However, severe mutations which result in protein truncation (such as frame shifts) are actually negatively selected for - meaning that tumours are observed to have fewer such mutations than expected by chance. Although low heteroplasmy levels of such mutations are tolerable, cells which cannot generate sufficient energy output have a lower fitness and are selected against.