Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis

Rong Na, Yishuo Wu, Guangliang Jiang, Hongjie Yu, Xiaoling Lin, Meilin Wang, Carly A. Conran, Richard J. Fantus, Ning Zhang, Shenghua Liu, Brian T. Helfand, Siqun L. Zheng, William B Isaacs, Qiang Ding, Zhoujun Shen, Jianfeng Xu

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)808-813
Number of pages6
JournalBJU International
Volume122
Issue number5
DOIs
StatePublished - Nov 1 2018

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Germ-Line Mutation
Urinary Bladder Neoplasms
DNA Repair
Mutation
Genes
Databases
Mutation Rate
Exome
Population Control
Age of Onset
Virulence
Urinary Bladder
Genome
Recurrence
Muscles
DNA
Population

Keywords

  • bladder cancer
  • DNA repair genes
  • germline
  • mutation

ASJC Scopus subject areas

  • Urology

Cite this

Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis. / 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.

In: BJU International, Vol. 122, No. 5, 01.11.2018, p. 808-813.

Research output: Contribution to journalArticle

Na, R, Wu, Y, Jiang, G, Yu, H, Lin, X, Wang, M, Conran, CA, Fantus, RJ, Zhang, N, Liu, S, Helfand, BT, Zheng, SL, Isaacs, WB, Ding, Q, Shen, Z & Xu, J 2018, 'Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis', BJU International, vol. 122, no. 5, pp. 808-813. https://doi.org/10.1111/bju.14370
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. / Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis. In: BJU International. 2018 ; Vol. 122, No. 5. pp. 808-813.
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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.",
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T1 - Germline mutations in DNA repair genes are associated with bladder cancer risk and unfavourable prognosis

AU - Na, Rong

AU - Wu, Yishuo

AU - Jiang, Guangliang

AU - Yu, Hongjie

AU - Lin, Xiaoling

AU - Wang, Meilin

AU - Conran, Carly A.

AU - Fantus, Richard J.

AU - Zhang, Ning

AU - Liu, Shenghua

AU - Helfand, Brian T.

AU - Zheng, Siqun L.

AU - Isaacs, William B

AU - Ding, Qiang

AU - Shen, Zhoujun

AU - Xu, Jianfeng

PY - 2018/11/1

Y1 - 2018/11/1

N2 - 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.

AB - 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.

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