title: Simultaneous DNA and RNA Mapping of Somatic Mitochondrial Mutations across Diverse Human Cancers.
abstract: Somatic mutations in the nuclear genome are required for tumor formation, but the functional consequences of somatic mitochondrial DNA (mtDNA) mutations are less understood. Here we identify somatic mtDNA mutations across 527 tumors and 14 cancer types, using an approach that takes advantage of evidence from both genomic and transcriptomic sequencing. We find that there is selective pressure against deleterious coding mutations, supporting that functional mitochondria are required in tumor cells, and also observe a strong mutational strand bias, compatible with endogenous replication-coupled errors as the major source of mutations. Interestingly, while allelic ratios in general were consistent in RNA compared to DNA, some mutations in tRNAs displayed strong allelic imbalances caused by accumulation of unprocessed tRNA precursors. The effect was explained by altered secondary structure, demonstrating that correct tRNA folding is a major determinant for processing of polycistronic mitochondrial transcripts. Additionally, the data suggest that tRNA clusters are preferably processed in the 3' to 5' direction. Our study gives insights into mtDNA function in cancer and answers questions regarding mitochondrial tRNA biogenesis that are difficult to address in controlled experimental systems.
authors.affiliation: Max Planck Institute for Biology of Ageing, Cologne, Germany.
authors.forename: James B
authors.initials: JB
authors.lastname: Stewart
authors.affiliation: Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Babak
authors.initials: B
authors.lastname: Alaei-Mahabadi
authors.affiliation: Center for non-coding RNA in Technology and Health, IKVH, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Sabarinathan
authors.affiliation: Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Tore
authors.initials: T
authors.lastname: Samuelsson
authors.affiliation: Center for non-coding RNA in Technology and Health, IKVH, University of Copenhagen, Frederiksberg, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Gorodkin
authors.affiliation: Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Claes M
authors.initials: CM
authors.lastname: Gustafsson
authors.affiliation: Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Larsson
mesh_terms: D000483:Alleles; D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm / Q000235:genetics; D054629:Genome, Mitochondrial; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D012334:RNA, Neoplasm; D012343:RNA, Transfer / Q000235:genetics; D017423:Sequence Analysis, RNA
chemical_list: D004272:DNA, Mitochondrial; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; D012343:RNA, Transfer