Comprehensive molecular characterization of mitochondrial genomes in human cancers

Abstract

Mitochondria are essential cellular organelles that play critical roles in cancer. Here, as part of the International Cancer Genome Consortium/The Cancer Genome Atlas Pan-Cancer Analysis of Whole Genomes Consortium, which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumor types, we performed a multidimensional, integrated characterization of mitochondrial genomes and related RNA sequencing data. Our analysis presents the most definitive mutational landscape of mitochondrial genomes and identifies several hypermutated cases. Truncating mutations are markedly enriched in kidney, colorectal and thyroid cancers, suggesting oncogenic effects with the activation of signaling pathways. We find frequent somatic nuclear transfers of mitochondrial DNA, some of which disrupt therapeutic target genes. Mitochondrial copy number varies greatly within and across cancers and correlates with clinical variables. Co-expression analysis highlights the function of mitochondrial genes in oxidative phosphorylation, DNA repair and the cell cycle, and shows their connections with clinically actionable genes. Our study lays a foundation for translating mitochondrial biology into clinical applications.

Dissecting the expression landscape of mitochondrial genes in lung squamous cell carcinoma and lung adenocarcinoma

“…encoded genes. The number of copies of mtDNA greatly affect the expression level of mitochondrial genes and this close association between mtDNA copy number and gene expression has been reported by Yuan et al (8) utilizing data from the International Cancer Genome Consortium and Reznik et al (11) using TCGA data. Additionally, certain host genes may also control mitochondrial gene expression (50).…”

“…Mitochondrial genome instability and impaired mitochondrial function are hallmarks of cancer progression (1)(2)(3). The somatic mutations and copy number variations in mitochondrial genomes have been frequently reported to be associated with the clinical stage of a tumor and notably affect the malignancy progression of lung cancer (4-7) and pan-adenocarcinoma (8). Furthermore, it has been demonstrated that a decrease in mitochondrial DNA (mtDNA) alters mitochondrial gene expression, resulting in a deficiency in oxidative phosphorylation, and this results in the disturbance of cellular functions (6,9).…”

An Innovative Data Analysis Strategy For Accurate NGS Detection of Tumor mtDNA Mutations

“…In addition to the default settings, we further explored the impact of three extra ltering strategies on mtDNA mutation calling: lter 1 removes C > A/G > T mutations with low MAF (1%) and strong sequence context bias (at CpCpN>CpApN, most frequently CpCpG>CpApG), which is known to arise from arti cial guanine oxidation during sequencing library preparation (18,19); lter 2 removes mtDNA mutations if the mutant-rate and mutant base-quality does not pass binominal test (P > 0.0001) (20,21); lter 3 removes mtDNA mutations if the MAF is smaller than the site-speci c threshold determined by site sequencing depth.…”

“…To reduce false positive mutations, several ltering strategies has commonly been applied (18). First, we assessed the effect of two ltering strategies previously reported on mtDNA mutation calling.…”

Quasi-Mendelian Paternal Inheritance of mitochondrial DNA: A notorious artifact, or anticipated mtDNA behavior?

“…Even simply large mtDNA fragments are very rare in the human nuclear genome. There are a few cases of almost full genome NUMTS -one recently detected in a cancer tissue (Yuan et al, 2017), one in a columbine monkey (Wang et al, 2015), but all of them contain at least some deletion. Moreover, NUMTs appear to be rather stable in the nuclear genomes of various species.…”