Cai Yun-Xi, Yang Xu, Lin Sheng, Xu Ya-Wen, Zhu Shan-Wen, Fan Dong-Mei, Zhao Min, Zhang Yuan-Bin, Yang Xue-Xi, Li Xin
Shenzhen Key Laboratory of Viral Oncology, The Clinical Innovation & Research Center (CIRC), Shenzhen Hospital, Southern Medical University, Shenzhen, 518110, People's Republic of China.
The Third School of Clinical Medicine, Southern Medical University, Guangzhou, 510500, People's Republic of China.
Cancer Manag Res. 2021 Feb 26;13:1943-1953. doi: 10.2147/CMAR.S295675. eCollection 2021.
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.
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.
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.
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.
染色体拷贝数畸变（CNA）是膀胱癌的一个标志，也是诊断探索的一个有用靶点。在此，我们构建了一种低覆盖度全基因组测序方法，用于检测膀胱癌患者尿沉渣DNA中的CNA。
我们进行了一项前瞻性研究，使用了65例膀胱肿瘤患者的尿沉渣样本，其中包括54例膀胱癌患者和11例膀胱良性肿瘤患者。纳入43名健康个体作为正常对照。从尿沉渣中提取DNA，并通过低覆盖度全基因组测序进行分析，以比较这三组之间CNA的差异。CNA由任意R值定义（正常范围±2）。当这些值超过正常范围的±0.2时，则怀疑存在增益/重复或缺失/缺失。
使用该方法，在51例膀胱癌患者中的39例、10例膀胱良性肿瘤患者中的2例以及39例正常对照中的8例检测到了CNA。膀胱癌患者DNA缺失和重复的长度明显大于膀胱良性肿瘤患者或正常对照（P<0.05）。膀胱癌重复CNA主要发生在染色体1q、5p、6p、7p、8q和13q上，而缺失主要发生在2q、8p、9q、9p和11p上。这些区域包含膀胱癌肿瘤相关基因，如STK3、COX6C、SPAG1、CDKAL1、C9orf53、CDKN2A、CDKN2B、MIR31和IFNAI。随访期间尿沉渣DNA中检测到的CNA数量明显减少。
我们的测序方法高度灵敏，能够检测到最小为0.15 Mb的染色体重复/微缺失变化。使用0.1~0.3×低覆盖度全基因组测序可用于检测尿沉渣DNA中的膀胱癌CNA。该方法为膀胱癌的无创诊断提供了一种有前景的方法，但仍需要在更大样本量中进一步验证。
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