Spectrum of somatic mitochondrial mutations in five cancers

Area of Science:

• Genomics
• Cancer Biology
• Mitochondrial Genetics

Background:

• Somatic mitochondrial DNA (mtDNA) mutations are observed in human tumors, but their prevalence and functional significance across diverse malignancies are not fully understood.
• Investigating the spectrum of mtDNA mutations is crucial for understanding their role in cancer development.

Purpose of the Study:

• To comprehensively analyze the spectrum of somatic and inherited mutations in the mitochondrial genome across five major cancer types.
• To determine the frequency and functional impact of tumor-specific somatic mtDNA mutations.

Main Methods:

• Whole-genome sequencing of paired tumor and normal tissue samples from 226 individuals across five cancer types.
• Analysis of somatic and inherited mitochondrial DNA variants using data from The Cancer Genome Atlas Research Network.

Main Results:

• Frequencies of deleterious somatic mtDNA mutations varied significantly by tumor type, from 13% in glioblastomas to 63% in rectal adenocarcinomas.
• Somatic mtDNA mutations were enriched for nonsynonymous changes and predicted to functionally impact encoded proteins compared to inherited variants.
• Sixty-five percent of somatic truncating mutations occurred in NADH dehydrogenase 5, with damaging mutations found across all cancer stages.

Conclusions:

• Damaging somatic mtDNA mutations are frequent in multiple cancer types and likely contribute to oncogenesis by conferring a selective advantage.
• The specific spectrum and frequency of somatic mtDNA mutations differ across tumor types, highlighting their varied roles in cancer progression.