Guangzhe Ge1,2, Ding Peng1,3,4,5, Bao Guan1,3,4,5, Yuanyuan Zhou1, Yanqing Gong3,4,5, Yue Shi1, Xueyu Hao1, Zhengzheng Xu1,2, Jie Qi1,2, Huan Lu1,2, Xiaoyun Zhang1,2, Yonghao Zhan3,4,5, Yifan Li3,4,5, Yucai Wu3,4,5, Guangpu Ding3,4,5, Qi Shen3,4,5, Qun He3,4,5, Xuesong Li3,4,5, Liqun Zhou3,4,5, Weimin Ci1,2,6. 1. Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. 2. University of Chinese Academy of Sciences, Beijing, China. 3. Department of Urology, Peking University First Hospital, Beijing, China. 4. Institute of Urology, Peking University, Beijing, China. 5. National Urological Cancer Center, Beijing, China. 6. Institute of Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
Abstract
BACKGROUND: Current noninvasive assays for urothelial carcinoma (UC) lack clinical sensitivity and specificity. Given the utility of plasma cell-free DNA (cfDNA) biomarkers, the development of urinary cfDNA biomarkers may improve the diagnostic sensitivity. METHODS: We assessed copy number alterations (CNAs) by shallow genome-wide sequencing of urinary cfDNA in 95 cancer-free individuals and 65 patients with UC, 58 with kidney cancer, and 45 with prostate cancer. We used a support vector machine to develop a diagnostic classifier based on CNA profiles to detect UC (UCdetector). The model was further validated in an independent cohort (52 patients). Genome sequencing data of tumor specimens from 90 upper tract urothelial cancers (UTUCs) and CNA data for 410 urothelial carcinomas of bladder (UCBs) from The Cancer Genome Atlas were used to validate the classifier. Genome sequencing data for urine sediment from 32 patients with UC were compared with cfDNA. To monitor the treatment efficacy, we collected cfDNA from 7 posttreatment patients. RESULTS: Urinary cfDNA was a more sensitive alternative to urinary sediment. The UCdetector could detect UC at a median clinical sensitivity of 86.5% and specificity of 94.7%. UCdetector performed well in an independent validation data set. Notably, the CNA features selected by UCdetector were specific markers for both UTUC and UCB. Moreover, CNA changes in cfDNA were consistent with the treatment effects. Meanwhile, the same strategy could localize genitourinary cancers to tissue of origin in 70.1% of patients. CONCLUSIONS: Our findings underscore the potential utility of urinary cfDNA CNA profiles as a basis for noninvasive UC detection and surveillance.
BACKGROUND: Current noninvasive assays for urothelial carcinoma (UC) lack clinical sensitivity and specificity. Given the utility of plasma cell-free DNA (cfDNA) biomarkers, the development of urinary cfDNA biomarkers may improve the diagnostic sensitivity. METHODS: We assessed copy number alterations (CNAs) by shallow genome-wide sequencing of urinary cfDNA in 95 cancer-free individuals and 65 patients with UC, 58 with kidney cancer, and 45 with prostate cancer. We used a support vector machine to develop a diagnostic classifier based on CNA profiles to detect UC (UCdetector). The model was further validated in an independent cohort (52 patients). Genome sequencing data of tumor specimens from 90 upper tract urothelial cancers (UTUCs) and CNA data for 410 urothelial carcinomas of bladder (UCBs) from The Cancer Genome Atlas were used to validate the classifier. Genome sequencing data for urine sediment from 32 patients with UC were compared with cfDNA. To monitor the treatment efficacy, we collected cfDNA from 7 posttreatment patients. RESULTS: Urinary cfDNA was a more sensitive alternative to urinary sediment. The UCdetector could detect UC at a median clinical sensitivity of 86.5% and specificity of 94.7%. UCdetector performed well in an independent validation data set. Notably, the CNA features selected by UCdetector were specific markers for both UTUC and UCB. Moreover, CNA changes in cfDNA were consistent with the treatment effects. Meanwhile, the same strategy could localize genitourinary cancers to tissue of origin in 70.1% of patients. CONCLUSIONS: Our findings underscore the potential utility of urinary cfDNA CNA profiles as a basis for noninvasive UC detection and surveillance.
Authors: Aadel A Chaudhuri; Bruna Pellini; Nadja Pejovic; Pradeep S Chauhan; Peter K Harris; Jeffrey J Szymanski; Zachary L Smith; Vivek K Arora Journal: JCO Precis Oncol Date: 2020-07-15
Authors: Bella Nguyen; Nicholas C Wong; Tim Semple; Michael Clark; Stephen Q Wong; Connull Leslie; Bob Mirzai; Michael Millward; Katie Meehan; Annette M Lim Journal: Sci Rep Date: 2021-02-17 Impact factor: 4.379