The Pattern of Natural Selection in Somatic Cancer Mutations of Human mtDNA
Department
Molecular and Cellular Biology
Document Type
Article
Publication Date
9-2010
Abstract
Tumors frequently contain somatic mutations in the mitochondrial DNA (mtDNA). Whether these mutations have a causal function or are merely an effect is still unclear. As tumor formation is a type of somatic evolution, we examine the cancer mutation pattern for consistency with random forces or selection. We also compare the tumor mutation pattern to that observed in the population to gain insight on the mutation process in cancer. Among germline mtDNAs, all genes show strong deficiency in missense changes, reflecting negative selection during human history. In somatic cancer sequences, mtDNA genes show relaxed negative selection relative to germline, or mutation consistent with neutrality. NADH dehydrogenase subunit 3, cytochrome c oxidase subunit 3 and NADH dehydrogenase subunit 4 L in particular show cancer missense mutation rates 9-18 times that of germline. Bootstrap analysis shows cytochrome B to have cancer changes in positions of unusually high conservation, suggesting that tumors select for mutations in residues of high functionality. Strong negative selection was detected in mitochondrially encoded cytochrome c oxidase 1 (MTCO1), suggesting that tumor cells are dependent upon MTCO1 function. Common population polymorphisms were also frequently reported among somatic tumor mutations. The implication of these 'somatic polymorphisms' in tumor growth is discussed.
Journal Title
Journal of Human Genetics
Journal ISSN
1434-5161
Volume
55
First Page
605
Last Page
612
Digital Object Identifier (DOI)
10.1038/jhg.2010.76