Simultaneous DNA and RNA Mapping of Somatic Mitochondrial Mutations Across Diverse Human Cancers

PLoS Genet. 2015 Jun 30;11(6):e1005333. doi: 10.1371/journal.pgen.1005333. eCollection 2015 Jun.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • DNA, Mitochondrial
  • DNA, Neoplasm / genetics
  • Genome, Mitochondrial
  • Humans
  • Mitochondria / genetics*
  • Mutation*
  • Neoplasms / genetics*
  • RNA, Neoplasm
  • RNA, Transfer / genetics
  • Sequence Analysis, RNA

Substances

  • DNA, Mitochondrial
  • DNA, Neoplasm
  • RNA, Neoplasm
  • RNA, Transfer

Grant support

EL was supported by The Swedish Foundation for Strategic Research (www.stratresearch.se), The Swedish Medical Research Council (www.vr.se), The Swedish Cancer Society, (www.cancerfonden.se), and The Åke Wiberg Foundation (www.ake-wiberg.se). CMG was supported by The Swedish Medical Research Council (www.vr.se), The Swedish Cancer Society, (www.cancerfonden.se), and The Knut and Alice Wallenberg Foundation (www.wallenberg.com/kaw). JG was supported by Innovation Fund Denmark (www.innovationsfonden.dk), The Danish Cancer Society (www.cancer.dk) The Danish Council for Independent Research, Technology and Production Sciences (http://ufm.dk/forskning-og-innovation/rad-og-udvalg/det-frie-forskningsrad) and The Danish Center for Scientific Computing (www.dcsc.dk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.