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Theranostics 2023; 13(1):324-338. doi:10.7150/thno.78718 This issue Cite

Research Paper

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

Wenjie Guo1#, Yang Liu1#, Xiaoying Ji1#, Shanshan Guo1, Fanfan Xie1, Yanxing Chen2, Kaixiang Zhou1, Huanqin Zhang1, Fan Peng1, Dan Wu1, Zhenni Wang1, Xu Guo1, Qi zhao2, Xiwen Gu3✉, Jinliang Xing1✉

1. State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.
2. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou, China.
3. State Key Laboratory of Cancer Biology and Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
#These authors contributed equally to this work.

✉ Corresponding authors: Jinliang Xing, Tel: +86-29-84774551; Fax: +86-29-84774551; E-mail: xingjledu.cn. Xiwen Gu, Tel: +86-29-84775497; Fax: +86-29-84775497; E-mail: xiwenguedu.cn.

Citation:
Guo W, Liu Y, Ji X, Guo S, Xie F, Chen Y, Zhou K, Zhang H, Peng F, Wu D, Wang Z, Guo X, zhao Q, Gu X, Xing J. Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer. Theranostics 2023; 13(1):324-338. doi:10.7150/thno.78718. https://www.thno.org/v13p0324.htm
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Abstract

Graphic 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.

Keywords: mitochondrial DNA, somatic mutations, evolutionary selection, metabolic remodeling, colorectal cancer

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APA
Guo, W., Liu, Y., Ji, X., Guo, S., Xie, F., Chen, Y., Zhou, K., Zhang, H., Peng, F., Wu, D., Wang, Z., Guo, X., zhao, Q., Gu, X., Xing, J. (2023). Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer. Theranostics, 13(1), 324-338. https://doi.org/10.7150/thno.78718.

ACS
Guo, W.; Liu, Y.; Ji, X.; Guo, S.; Xie, F.; Chen, Y.; Zhou, K.; Zhang, H.; Peng, F.; Wu, D.; Wang, Z.; Guo, X.; zhao, Q.; Gu, X.; Xing, J. Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer. Theranostics 2023, 13 (1), 324-338. DOI: 10.7150/thno.78718.

NLM
Guo W, Liu Y, Ji X, Guo S, Xie F, Chen Y, Zhou K, Zhang H, Peng F, Wu D, Wang Z, Guo X, zhao Q, Gu X, Xing J. Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer. Theranostics 2023; 13(1):324-338. doi:10.7150/thno.78718. https://www.thno.org/v13p0324.htm

CSE
Guo W, Liu Y, Ji X, Guo S, Xie F, Chen Y, Zhou K, Zhang H, Peng F, Wu D, Wang Z, Guo X, zhao Q, Gu X, Xing J. 2023. Mutational signature of mtDNA confers mechanistic insight into oxidative metabolism remodeling in colorectal cancer. Theranostics. 13(1):324-338.

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