Abstract A80: Somatic cancer mutations in human mtDNA show neutral and positive selection

Abstract

Abstract The majority of cancers exhibit somatic mutations in the mitochondrial chromosome (mtDNA). Whether these mutations play a causal role or are merely an effect is an issue of on-going uncertainty. To study the role of somatic mtDNA mutations in cancer, we present a meta-analysis of 356 tumor sequences of multiple cancer types from the literature. As tumor formation is a type of somatic evolution, we examine the mutation pattern for whether the cancer DNA variation is consistent with drift (random forces) or selection. We also compare the cancer mutation pattern to that observed at the organismal or population level in order to gain insight on the mutation process in cancer cells. Among germline sequences, all mtDNA genes show a strong deficiency of amino acid changes, reflecting negative selection during human history and consistent with functional constraints at the organismal level. In somatic cancer sequences, mtDNA genes show either relaxed negative selection relative to germline or a mutation pattern consistent with neutrality. ND3, CO3, and ND4L in particular show cancer missense mutation rates nine - 18 times that of their counterpart genes at the germline level. Bootstrap analysis of the cancer-specific missense mutations show Cytochrome B and ND6 to have changes occurring in positions of unusually high conservation, suggesting that tumors select for mutations in residues of high functionality. These results support relaxed negative selection or neutrality for somatic mtDNA mutations in cancer, with the later potential for positive selection of alterations that impair mitochondrial function. Citation Information: Cancer Res 2009;69(23 Suppl):A80.