Introduction:

Germline BRCA1 and BRCA2 mutations are known to be associated with breast, ovarian, cervical, stomach, pancreatic, and prostate cancer. Urothelial carcinomas are not usually considered part of the BRCA spectrum of tumors. However, we have identified several patients in whom urothelial carcinoma was part of a germline BRCA mutation phenotype. We present our experience with such cases and compare our findings with those from The Cancer Genome Atlas (TCGA). Identifying germline BRCA mutations in patients with urothelial carcinoma not only affects screening for, and the prevention of, other non-urothelial cancers in these patients but might also affect their disease course.

Methods:

After IRB approval, we identified 5 patients with a personal history of urothelial carcinoma as well as a germline BRCA1 or BRCA2 mutation. The specific BRCA1 or BRCA2 mutations were compared to somatic mutations in the same genes in the 412 patient TCGA muscle-invasive bladder cancer cohort using cBioPortal and the associated MutationMapper. Presumptive protein-level modifications from such germline mutations were identified from DNA mutation data using Ensembl and ClinVar datasets. We also evaluated the pathogenic and nominated pathogenic BRCA mutations found in a similar but distinct 411 patient TCGA (PanCancer Atlas) cohort focused specifically on germline mutations in the context of our own cohort. Mutations of uncertain significance were excluded from our analysis.

Results:

Within our institutional cohort of five patients, we identified three patients with mutations in BRCA1 and two with mutations in BRCA2. These patients were younger at presentation than typical urothelial carcinoma patients (median = 59). Four had non-muscle invasive bladder cancer and one had muscle-invasive bladder cancer. Four patients in our cohort had family histories of BRCA-associated malignancies, including one patient with a family member with bladder cancer. In contrast to our institutional cohort, none of the pathogenic or likely pathogenic somatic mutations in the TCGA cohort were identified in patients with low grade cancer (Figure 1a). However, one of the two nominated variants in the TCGA (PanCancer Atlas) germline cohort was associated with low grade cancer.

We compared our five patients with 17 patients in the TCGA (Cell, 2017) and four patients in the TCGA (PanCancer Atlas) cohorts with known or nominated pathogenic BRCA mutations. We depicted these mutations by BRCA gene (Figure 1b). All documented mutations were unique across cohorts aside from two patients with the same BRCA2 mutation in our institutional cohort.

With respect to influence on behavior, we noted in our institutional cohort that two of the five patients were diagnosed with their BRCA mutation in their 30s, and before diagnosis of any other malignancy. As a consequence, they initiated screening for BRCA-associated malignancies as per guidelines.

Conclusion:

We identified four unique germline BRCA mutations associated with urothelial carcinoma. The association of these mutations with treatments and outcomes are limited by the early stage in genomic characterization of urothelial carcinoma, as well as their infrequency and variability. Although rare, germline BRCA mutations are observed in bladder cancer patients, and identification of this mutation could impact the patient’s overall screening. Further study may elucidate whether patients who are diagnosed with BRCA mutations should be monitored more closely for urothelial carcinoma with the aim of shifting diagnosis earlier in the disease pathway.

Funding: NA