Mutational profiling of mtDNA control region reveals tumor-specific evolutionary selection involved in mitochondrial dysfunction

Background Mitochondrial DNA (mtDNA) mutations alter mitochondrial function in oxidative metabolism and play an important role in tumorigenesis. A series of studies have demonstrated that the mtDNA control region (mtCTR), which is essential for mtDNA replication and transcription, represents a mutational hotspot in human tumors. However, a comprehensive pan-cancer evolutionary pattern analysis of mtCTR mutations is urgently needed. Methods We generated a comprehensive combined dataset containing 10026 mtDNA somatic mutations from 4664 patients, covering 20 tumor types based on public and private next-generation sequencing data. Findings Our results demonstrated a significantly higher and much more variable mutation rate in mtCTR than in the coding region across different tumor types. Moreover, our data showed a remarkable distributional bias of tumor somatic mutations between the hypervariable segment (HVS) and non-HVS, with a significantly higher mutation density and average mutation sites in HVS. Importantly, the tumor-specific mutational pattern between mtCTR HVS and non-HVS was identified, which was classified into three evolutionary selection types (relaxed, moderate, and strict constraint types). Analysis of substitution patterns revealed that the prevalence of CH > TH in non-HVS greatly contributed to the mutational selection pattern of mtCTR across different tumor types. Furthermore, we found that the mutational pattern of mtCTR in the four tumor types was clearly associated with mitochondrial biogenesis, mitochondrial oxidative metabolism, and the overall survival of patients. Interpretation Our results suggest that somatic mutations in mtCTR may be shaped by tumor-specific selective pressure and are involved in tumorigenesis. Copyright (c) 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Automated summary

The study reveals a significantly higher and more variable mutation rate in mtCTR across different tumor types, with a noticeable distributional bias of tumor somatic mutations between the hypervariable segment and non-hypervariable segment. The mutational pattern of mtCTR is associated with mitochondrial biogenesis, mitochondrial oxidative metabolism, and patient overall survival.