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Low-Coverage Sequencing of Urine Sediment DNA for Detection of Copy Number Aberrations in Bladder Cancer

Authors Cai YX, Yang X, Lin S, Xu YW, Zhu SW, Fan DM, Zhao M, Zhang YB, Yang XX, Li X

Received 9 December 2020

Accepted for publication 15 January 2021

Published 26 February 2021 Volume 2021:13 Pages 1943—1953


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Eileen O'Reilly

Yun-xi Cai,1,2,* Xu Yang,1,2,* Sheng Lin,3 Ya-wen Xu,4,* Shan-wen Zhu,5 Dong-mei Fan,6 Min Zhao,7 Yuan-bin Zhang,1,2 Xue-xi Yang,6 Xin Li1,2

1Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, 518110, People’s Republic of China; 2The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510500, People’s Republic of China; 3Laboratory of Molecular Medicine, Shenzhen Health Development Research Center, Shenzhen, 518040, People’s Republic of China; 4Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, 510000, People’s Republic of China; 5Reproductive Medicine Center, Huizhou Central People’s Hospital, Huizhou, 516000, People’s Republic of China; 6Institute of Antibody Engineering, School of Laboratory Medical and Biotechnology, Southern Medical University, Guangzhou, 510515, People’s Republic of China; 7PANACRO (Hefei) Pharmaceutical Technology Co., Ltd., Hefei, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Xin Li
Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, 1333 Xinhu Road, Baoan District, Shenzhen, Guangdong, 518102, People’s Republic of China
Email [email protected]
Xue-xi Yang
Institute of Antibody Engineering, School of Laboratory Medicine and Biotechnology, Southern Medical University, 1838 North Guangzhou Road, Guangzhou, Guangdong, 510515, People’s Republic of China
Email [email protected]

Purpose: Chromosomal copy number aberrations (CNAs) are a hallmark of bladder cancer and a useful target for diagnostic explorations. Here we constructed a low-coverage whole-genome sequencing method for the detection of CNAs in urine sediment DNA from patients with bladder cancer.
Patients and Methods: We conducted a prospective study using urine sediment samples from 65 patients with bladder tumors, including 54 patients with bladder cancer and 11 patients with benign bladder tumors. Forty-three healthy individuals were included as normal controls. DNA was extracted from urine sediments and analyzed by low-coverage whole-genome sequencing to compare differences in CNAs among these three groups. CNAs are defined by arbitrary R values (normal range ± 2). When these values exceed ± 0.2 of normal range, gain/duplication or loss/deletion are suspected.
Results: With this method, CNAs were detected in 39 of 51 patients with bladder cancer, 2 of 10 patients with benign bladder tumors, and 8 of 39 normal controls. The lengths of DNA deletion and duplication were significantly larger in patients with bladder cancer than in patients with benign tumors or normal controls (P < 0.05). Bladder cancer duplicate CNAs mainly occurred on chromosomes 1q, 5p, 6p, 7p, 8q, and 13q, while deletions mainly occurred on 2q, 8p, 9q, 9p, and 11p. Those regions contained bladder cancer tumor-related genes, such as STK3, COX6C, SPAG1, CDKAL1, C9orf53, CDKN2A, CDKN2B, MIR31, and IFNA1. The number of CNAs detected in urine sediment DNA during the follow-up period was significantly reduced.
Conclusion: Our sequencing method is highly sensitive and can detect a minimal chromosome repeat/microdeletion change of 0.15 Mb. The use of 0.1∼ 0.3× low-coverage whole-genome sequencing can be used to detect bladder cancer CNAs in urine sediment DNA. This method provides a promising method for noninvasive diagnosis of bladder cancer, but still needs further verification in a larger sample size.

Keywords: bladder cancer, urine sediment DNA, next-generation sequence, copy number aberrations

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