RT Journal Article
SR Electronic
T1 Noninvasive Detection of Urothelial Carcinoma by Cost-effective Low-coverage Whole-genome Sequencing from Urine-Exfoliated Cell DNA
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 5646
OP 5654
DO 10.1158/1078-0432.CCR-20-0401
VO 26
IS 21
A1 Zeng, Shuxiong
A1 Ying, Yidie
A1 Xing, Naidong
A1 Wang, Baiyun
A1 Qian, Ziliang
A1 Zhou, Zunlin
A1 Zhang, Zhensheng
A1 Xu, Weidong
A1 Wang, Huiqing
A1 Dai, Lihe
A1 Gao, Li
A1 Zhou, Tie
A1 Ji, Jiatao
A1 Xu, Chuanliang
YR 2020
UL http://clincancerres.aacrjournals.org/content/26/21/5646.abstract
AB Purpose: Urothelial carcinoma is a malignant cancer with frequent chromosomal aberrations. Here, we investigated the application of a cost-effective, low-coverage whole-genome sequencing technology in detecting all chromosomal aberrations.Experimental Design: Patients with urothelial carcinomas and nontumor controls were prospectively recruited in clinical trial NCT03998371. Urine-exfoliated cell DNA was analyzed by Illumina HiSeq XTen, followed by genotyping with a customized bioinformatics workflow named Urine Exfoliated Cells Copy Number Aberration Detector (UroCAD).Results: In the discovery phase, urine samples from 126 patients with urothelial carcinomas and 64 nontumor disease samples were analyzed. Frequent chromosome copy-number changes were found in patients with tumor as compared with nontumor controls. A novel diagnosis model, UroCAD, was built by incorporating all the autosomal chromosomal changes. The model reached performance of AUC = 0.92 (95% confidence interval, 89.4%–97.3%). At the optimal cutoff, |Z| ≥ 3.21, the sensitivity, specificity, and accuracy were 82.5%, 96.9%, and 89.0%, respectively. The prediction positivity was found correlated with tumor grade (P = 0.01). In the external validation cohort of 95 participants, the UroCAD assay identified urothelial carcinomas with an overall sensitivity of 80.4%, specificity of 94.9%, and AUC of 0.91. Meanwhile, UroCAD assay outperformed cytology tests with significantly improved sensitivity (80.4% vs. 33.9%; P < 0.001) and comparable specificity (94.9% vs. 100%; P = 0.49).Conclusions: UroCAD could be a robust urothelial carcinoma diagnostic method with improved sensitivity and similar specificity as compared with cytology tests. It may be used as a noninvasive approach for diagnosis and recurrence surveillance in urothelial carcinoma prior to the use of cystoscopy, which would largely reduce the burden on patients.