Rong Na1,2,3, Yishuo Wu1,2, Guangliang Jiang1, Hongjie Yu2, Xiaoling Lin1, Meilin Wang4, Carly A Conran2, Richard J Fantus2,5, Ning Zhang1, Shenghua Liu1, Brian T Helfand2, Siqun L Zheng2, William B Isaacs6,7, Qiang Ding1, Zhoujun Shen1, Jianfeng Xu1,2. 1. Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China. 2. Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, IL, USA. 3. Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 4. State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China. 5. Division of Urology, Department of Surgery, University of Chicago Medical Center, Chicago, IL, USA. 6. Department of Urology, James Buchanan Brady Urologic Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA. 7. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
Abstract
OBJECTIVES: To perform a systematic evaluation of whether germline DNA repair gene mutations in bladder cancer (BCa) are associated with increased risk of BCa and aggressive disease. MATERIALS AND METHODS: Germline DNA from 98 patients with BCa was analysed for 54 DNA repair genes using a customized targeted sequencing panel. Population control data were obtained from the public databases the Exome Aggregation Consortium database and the Genome Aggregation Database. Mutation pathogenicity was annotated based on American College of Medical Genetics criteria, mutation frequencies in the general population and the ClinVar database. Mutation frequencies were compared based on case-control and case-case designs for disease risks, disease aggressiveness and outcomes. RESULTS: The frequency of pathogenic/likely pathogenic germline DNA repair gene mutations was 10.2% among patients with BCa. Within the subset of patients with carcinoma invading the bladder muscle, the frequency was 15.8%, ~2.4-fold higher than in patients with non-muscle invasive BCa (6.67%). The mutation frequency among patients with early-onset disease (at age <45 years) was ~3-fold higher than among those diagnosed after age 45 years (28.57% vs 8.79%). Mutation carriers had a significantly higher frequency of unfavourable clinical outcomes (disease recurrence or progression to metastatic BCa) than non-carriers (50.0% vs 13.64%; P = 0.013). CONCLUSION: Pathogenic and likely pathogenic mutations in DNA repair genes were associated with unfavourable prognosis of BCa.
OBJECTIVES: To perform a systematic evaluation of whether germline DNA repair gene mutations in bladder cancer (BCa) are associated with increased risk of BCa and aggressive disease. MATERIALS AND METHODS: Germline DNA from 98 patients with BCa was analysed for 54 DNA repair genes using a customized targeted sequencing panel. Population control data were obtained from the public databases the Exome Aggregation Consortium database and the Genome Aggregation Database. Mutation pathogenicity was annotated based on American College of Medical Genetics criteria, mutation frequencies in the general population and the ClinVar database. Mutation frequencies were compared based on case-control and case-case designs for disease risks, disease aggressiveness and outcomes. RESULTS: The frequency of pathogenic/likely pathogenic germline DNA repair gene mutations was 10.2% among patients with BCa. Within the subset of patients with carcinoma invading the bladder muscle, the frequency was 15.8%, ~2.4-fold higher than in patients with non-muscle invasive BCa (6.67%). The mutation frequency among patients with early-onset disease (at age <45 years) was ~3-fold higher than among those diagnosed after age 45 years (28.57% vs 8.79%). Mutation carriers had a significantly higher frequency of unfavourable clinical outcomes (disease recurrence or progression to metastatic BCa) than non-carriers (50.0% vs 13.64%; P = 0.013). CONCLUSION: Pathogenic and likely pathogenic mutations in DNA repair genes were associated with unfavourable prognosis of BCa.
Authors: Kim E Nichols; Chimene A Kesserwan; Jamie L Maciaszek; Ninad Oak; Wenan Chen; Kayla V Hamilton; Rose B McGee; Regina Nuccio; Roya Mostafavi; Stacy Hines-Dowell; Lynn Harrison; Leslie Taylor; Elsie L Gerhardt; Annastasia Ouma; Michael N Edmonson; Aman Patel; Joy Nakitandwe; Alberto S Pappo; Elizabeth M Azzato; Sheila A Shurtleff; David W Ellison; James R Downing; Melissa M Hudson; Leslie L Robison; Victor Santana; Scott Newman; Jinghui Zhang; Zhaoming Wang; Gang Wu Journal: Cold Spring Harb Mol Case Stud Date: 2019-10-23
Authors: Aram Vosoughi; Tuo Zhang; Kyrillus S Shohdy; Panagiotis J Vlachostergios; David C Wilkes; Bhavneet Bhinder; Scott T Tagawa; David M Nanus; Ana M Molina; Himisha Beltran; Cora N Sternberg; Samaneh Motanagh; Brian D Robinson; Jenny Xiang; Xiao Fan; Wendy K Chung; Mark A Rubin; Olivier Elemento; Andrea Sboner; Juan Miguel Mosquera; Bishoy M Faltas Journal: Nat Commun Date: 2020-12-03 Impact factor: 14.919
Authors: Elżbieta Złowocka-Perłowska; Aleksandra Tołoczko-Grabarek; Steven A Narod; Jan Lubiński Journal: Hered Cancer Clin Pract Date: 2022-04-08 Impact factor: 2.857
Authors: Qun-Xian Zhang; Ye Yang; Heng Yang; Qiang Guo; Jia-Long Guo; Hua-Song Liu; Jun Zhang; Dan Li Journal: Transl Cancer Res Date: 2021-10 Impact factor: 1.241