Premium
Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis
Author(s) -
Na Rong,
Wu Yishuo,
Jiang Guangliang,
Yu Hongjie,
Lin Xiaoling,
Wang Meilin,
Conran Carly A.,
Fantus Richard J.,
Zhang Ning,
Liu Shenghua,
Helfand Brian T.,
Zheng Siqun L.,
Isaacs William B.,
Ding Qiang,
Shen Zhoujun,
Xu Jianfeng
Publication year - 2018
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/bju.14370
Subject(s) - germline mutation , germline , dna repair , mutation , bladder cancer , population , exome , disease , gene , cancer , dna mismatch repair , exome sequencing , biology , genetics , medicine , environmental health
Objectives To perform a systematic evaluation of whether germline DNA repair gene mutations in bladder cancer ( BC a) are associated with increased risk of BC a and aggressive disease. Materials and Methods Germline DNA from 98 patients with BC a 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 BC a. 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 BC a (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 BC a) 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.