Journal
BJU INTERNATIONAL
Volume 122, Issue 5, Pages 808-813Publisher
WILEY
DOI: 10.1111/bju.14370
Keywords
bladder cancer; germline; mutation; DNA repair genes
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Funding
- Shanghai Hospital Development Centre [SHDC12015105]
- National Natural Science Foundation of China [81472379, 81402339]
- John and Carol Walter Fund for Personalized Cancer Care at NorthShore University HealthSystem
- Ellrodt-Schweighauser family
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ObjectivesMaterials and MethodsTo 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. 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. ResultsConclusionThe frequency of pathogenic/likely pathogenic germlineDNA repair gene mutations was 10.2% among patients with BCa. Within the subset of patients withcarcinoma invading the bladder muscle, the frequency was 15.8%, similar to 2.4-fold higher than in patients with non-muscle invasive BCa (6.67%). The mutation frequencyamong patients with early-onset disease (at age <45years) was similar to 3-fold higher than among those diagnosedafter age 45years (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). Pathogenic and likely pathogenic mutations in DNA repair genes were associated with unfavourable prognosis of BCa.
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