Dataset Information

Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer.

ABSTRACT: Rationale: Mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) mutations and subsequent metabolic defects are closely involved in tumorigenesis and progression in a cancer-type specific manner. To date, the mutational pattern of mtDNA somatic mutations in colorectal cancer (CRC) tissues and its clinical implication are still not completely clear. Methods: In the present study, we generated a large mtDNA somatic mutation dataset from three CRC cohorts (432, 1,015, and 845 patients, respectively) and then most comprehensively characterized the CRC-specific evolutionary pattern and its clinical implication. Results: Our results showed that the mtDNA control region (mtCTR) with a high mutation density exhibited a distinct mutation spectrum characterizing a high enrichment of L-strand C > T mutations, which was contrary to the H-strand C > T mutational bias observed in the mtDNA coding region (mtCDR) (P < 0.001). Further analysis clearly confirmed the relaxed evolutionary selection of mtCTR mutations, which was mainly characterized by the similar distribution of hypervariable region (HVS) and non-HVS mutation density. Moreover, significant negative selection was identified in mutations of mtDNA complex V (ATP6/ATP8) and tRNA loop regions. Although our data showed that oxidative metabolism was commonly increased in CRC cells, mtDNA somatic mutations in CRC tissues were not closely associated with mitochondrial biogenesis, oxidative metabolism, and clinical progression, suggesting a cancer-type specific relationship between mtDNA mutations and mitochondrial metabolic functions in CRC cells. Conclusion: Our study identified the CRC-specific evolutionary mode of mtDNA mutations, which is possibly matched to specific mitochondrial metabolic remodeling and confers new mechanic insight into CRC tumorigenesis.

SUBMITTER: Guo W

PROVIDER: S-EPMC9800724 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer.

Guo Wenjie W Liu Yang Y Ji Xiaoying X Guo Shanshan S Xie Fanfan F Chen Yanxing Y Zhou Kaixiang K Zhang Huanqin H Peng Fan F Wu Dan D Wang Zhenni Z Guo Xu X Zhao Qi Q Gu Xiwen X Xing Jinliang J

Theranostics 20230101 1

<b>Rationale:</b> Mitochondrial dysfunction caused by mitochondrial DNA (mtDNA) mutations and subsequent metabolic defects are closely involved in tumorigenesis and progression in a cancer-type specific manner. To date, the mutational pattern of mtDNA somatic mutations in colorectal cancer (CRC) tissues and its clinical implication are still not completely clear. <b>Methods:</b> In the present study, we generated a large mtDNA somatic mutation dataset from three CRC cohorts (432, 1,015, and 845 ...[more]

PMID: 36593960

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Dataset Information

Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer.

Publications

Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer.

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