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Zhou K, Liu Y, Yuan Q, et al. Next-Generation Sequencing-Based Analysis of Urine Cell-Free mtDNA Reveals Aberrant Fragmentation and Mutation Profile in Cancer Patients. Clin Chem. 2022;doi: 10.1093/clinchem/hvab268.
Zhou, K., Liu, Y., Yuan, Q., Lai, D., Guo, S., Wang, Z., Su, L., Zhang, H., Wang, X., Guo, W., Ji, X., Gu, X., Huang, Q., Guo, X., & Xing, J. (2022). Next-Generation Sequencing-Based Analysis of Urine Cell-Free mtDNA Reveals Aberrant Fragmentation and Mutation Profile in Cancer Patients. Clinical chemistry, . https://doi.org/10.1093/clinchem/hvab268
Zhou, Kaixiang, et al. "Next-Generation Sequencing-Based Analysis of Urine Cell-Free mtDNA Reveals Aberrant Fragmentation and Mutation Profile in Cancer Patients." Clinical chemistry vol. (2022). doi: https://doi.org/10.1093/clinchem/hvab268
Zhou K, Liu Y, Yuan Q, Lai D, Guo S, Wang Z, Su L, Zhang H, Wang X, Guo W, Ji X, Gu X, Huang Q, Guo X, Xing J. Next-Generation Sequencing-Based Analysis of Urine Cell-Free mtDNA Reveals Aberrant Fragmentation and Mutation Profile in Cancer Patients. Clin Chem. 2022 Jan 05; doi: 10.1093/clinchem/hvab268. Epub 2022 Jan 05. PMID: 34993545.
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Clin Chem. 2022 Jan 05; doi: 10.1093/clinchem/hvab268. Epub 2022 Jan 05.

Next-Generation Sequencing-Based Analysis of Urine Cell-Free mtDNA Reveals Aberrant Fragmentation and Mutation Profile in Cancer Patients.

Clinical chemistry

Kaixiang Zhou, Yang Liu, Qing Yuan, Dong Lai, Shanshan Guo, Zhenni Wang, Liping Su, Huanqin Zhang, Xiangxu Wang, Wenjie Guo, Xiaoying Ji, Xiwen Gu, Qichao Huang, Xu Guo, Jinliang Xing

Affiliations

  1. State Key Laboratory of Cancer Biology and Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, China.
  2. Institute of Medical Research, Northwestern Polytechnical University, Xi'an, China.
  3. Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  4. Department of Medical Technology, College of Medical Technology, Shaanxi University of Chinese Medicine, Xianyang, China.
  5. Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, Department of Stomatology Research Center, Xi'an Jiaotong University College of Stomatology, Xi'an, China.

PMID: 34993545 DOI: 10.1093/clinchem/hvab268

Abstract

BACKGROUND: Many studies have demonstrated the high efficacy of cell-free nuclear DNA in cancer diagnostics. Compared to nuclear DNA, mitochondrial DNA (mtDNA) exhibits distinct characteristics, including multiple copies per cell and higher mutation frequency. However, the potential applicability of cell-free mtDNA (cf-mtDNA) in plasma and urine remains poorly investigated.

METHODS: Here, we comprehensively analyzed the fragmentomic and mutational characteristics of cf-mtDNA in urine and plasma samples from controls and cancer patients using next-generation sequencing.

RESULTS: Compared to plasma cf-mtDNA, urine cf-mtDNA exhibited increased copy numbers and wider spread in fragment size distributions. Based on 2 independent animal models, urine cf-mtDNA originated predominantly from local shedding and transrenal excretion. Further analysis indicated an enhanced fragmentation of urine cf-mtDNA in renal cell carcinoma (RCC) and colorectal cancer (CRC) patients. Using the mtDNA sequence of peripheral blood mononuclear cells for reference, the mutant fragments were shorter than wild-type fragments in urine cf-mtDNA. Size selection of short urine cf-mtDNA fragments (<150 bp) significantly enhanced the somatic mutation detection. Our data revealed remarkably different base proportions of fragment ends between urine and plasma cf-mtDNA that also were associated with fragment size. Moreover, both RCC and CRC patients exhibited significantly higher T-end and lower A-end proportions in urine cf-mtDNA than controls. By integrating the fragmentomic and mutational features of urine cf-mtDNA, our nomogram model exhibited a robust efficacy for cancer diagnosis.

CONCLUSIONS: Our proof-of-concept findings revealed aberrant fragmentation and mutation profiles of urine cf-mtDNA in cancer patients that have diagnostic potential.

© American Association for Clinical Chemistry 2022. All rights reserved. For permissions, please email: [email protected].

Keywords: cancer; cell-free mtDNA; fragmentomics; liquid biopsy; next-generation sequencing; urine

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