Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer.
Ju YS., Alexandrov LB., Gerstung M., Martincorena I., Nik-Zainal S., Ramakrishna M., Davies HR., Papaemmanuil E., Gundem G., Shlien A., Bolli N., Behjati S., Tarpey PS., Nangalia J., Massie CE., Butler AP., Teague JW., Vassiliou GS., Green AR., Du MQ., Unnikrishnan A., Pimanda JE., Teh BT., Munshi N., Greaves M., Vyas P., El-Naggar AK., Santarius T., Collins VP., Grundy R., Taylor JA., Hayes DN., Malkin D., Foster CS., Warren AY., Whitaker HC., Brewer D., Eeles R., Cooper C., Neal D., Visakorpi T., Isaacs WB., Bova GS., Flanagan AM., Futreal PA., Lynch AG., Chinnery PF., McDermott U., Stratton MR., Campbell PJ.
Recent sequencing studies have extensively explored the somatic alterations present in the nuclear genomes of cancers. Although mitochondria control energy metabolism and apoptosis, the origins and impact of cancer-associated mutations in mtDNA are unclear. In this study, we analyzed somatic alterations in mtDNA from 1675 tumors. We identified 1907 somatic substitutions, which exhibited dramatic replicative strand bias, predominantly C > T and A > G on the mitochondrial heavy strand. This strand-asymmetric signature differs from those found in nuclear cancer genomes but matches the inferred germline process shaping primate mtDNA sequence content. A number of mtDNA mutations showed considerable heterogeneity across tumor types. Missense mutations were selectively neutral and often gradually drifted towards homoplasmy over time. In contrast, mutations resulting in protein truncation undergo negative selection and were almost exclusively heteroplasmic. Our findings indicate that the endogenous mutational mechanism has far greater impact than any other external mutagens in mitochondria and is fundamentally linked to mtDNA replication.