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

Xiaoying Ji; Wenjie Guo; Xiwen Gu; Shanshan Guo; Kaixiang Zhou; Liping Su; Qing Yuan; Yang Liu; Xu Guo; Qichao Huang; Jinliang Xing

doi:10.1016/j.ebiom.2022.104058

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

EBioMedicine. 2022 Jun:80:104058. doi: 10.1016/j.ebiom.2022.104058. Epub 2022 May 17.

Authors

Xiaoying Ji¹, Wenjie Guo¹, Xiwen Gu², Shanshan Guo¹, Kaixiang Zhou¹, Liping Su¹, Qing Yuan³, Yang Liu¹, Xu Guo¹, Qichao Huang⁴, Jinliang Xing⁵

Affiliations

¹ State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.
² Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Clinical Research Center of Shaanxi Province for Dental and Maxillofacial Diseases, College of Stomatology, Xi'an Jiaotong University, Xi'an, China.
³ Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China.
⁴ State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.. Electronic address: huangqichao1@163.com.
⁵ State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.. Electronic address: xingjinliang@163.com.

Abstract

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 C_H > T_H 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.

Fundings: National Natural Science Foundation of China [grants 82020108023, 81830070, 81872302], and Autonomous Project of State Key Laboratory of Cancer Biology, China [grants CBSKL2019ZZ06, CBSKL2019ZZ27].

Keywords: Control region; Evolutionary selection; Hypervariable segment; Mitochondrial DNA; Somatic mutation.

MeSH terms

Carcinogenesis
Cell Transformation, Neoplastic
DNA Mutational Analysis
DNA, Mitochondrial* / genetics
Humans
Mitochondria / genetics
Mutation
Neoplasms* / genetics

Substances

DNA, Mitochondrial