Germline Mutations in DNA Repair Genes are Associated with Bladder Cancer Risk and Unfavorable Prognosis.

Na R1,2,3, Wu Y1,2, Jiang G1, Yu H2, Lin X1, Wang M4, Conran CA2, Fantus RJ2,5, Zhang N1, Liu S1, Helfand BT2, Zheng SL2, Isaacs WB6,7, Ding Q1, Shen Z1, Xu J1,2.

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Abstract

OBJECTIVES:

Germline DNA repair gene mutations in bladder cancer (BCa) are poorly characterized. We therefore sought to perform a systematic evaluation of whether these mutations are associated with increased risk of BCa and aggressive disease.

MATERIALS AND METHODS:

Germline DNA from 98 BCa patients was analyzed for 54 DNA repair genes using a customized targeted sequencing panel. Population control data were obtained from the public databases Exome Aggregation Consortium database (ExAC) and Genome Aggregation Database (gnomAD). Mutation pathogenicity was annotated based on American College of Medical Genetics (ACMG) 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 10.20% among BCa patients. Within the subset of subjects with muscle invasive bladder cancer (MIBC), the frequency was 15.8%, ~2.4-fold higher than subjects with non-muscle invasive bladder cancer (6.67%, NMIBC). The mutation frequency among subjects with early onset disease (<45 yr) was ~3-fold higher than those diagnosed after age ≥45 yr (28.57% vs. 8.79%). Mutation carriers had a significantly higher frequency of unfavorable clinical outcomes (disease recurrence or progression to metastatic BCa) than non-carriers (50.00% vs. 13.64%, P=0.013).