Incidence of Germline Variants in Familial Bladder Cancer and Among Patients With Cancer Predisposition Syndromes.

TitleIncidence of Germline Variants in Familial Bladder Cancer and Among Patients With Cancer Predisposition Syndromes.
Publication TypeJournal Article
Year of Publication2022
AuthorsMossanen M, Nassar AH, Stokes SM, Martinez-Chanza N, Kumar V, Nuzzo PVitale, Kwiatkowski DJ, Garber JE, Curran C, Freeman D, Preston M, Mouw KW, Kibel A, Choueiri TK, Sonpavde G, Rana HQ
JournalClin Genitourin Cancer
Date Published2022 Dec
KeywordsGenetic Predisposition to Disease, Germ Cells, Germ-Line Mutation, Humans, Incidence, Retrospective Studies, Urinary Bladder Neoplasms

BACKGROUND: The familial aggregation of bladder cancers has been observed, but the incidence and association of familial bladder cancer with germline pathogenic and likely pathogenic (P/LP) variants is unknown.

PATIENTS AND METHODS: A retrospective analysis was conducted of patients with bladder cancer treated at the Dana-Farber Cancer Institute to identify those with a first-degree relative with bladder cancer. A second cohort of patients referred to DFCI for suspicion of a cancer predisposition syndrome was analyzed for candidate P/LP germline variants. Descriptive statistics were generated.

RESULTS: Among 885 patients with bladder cancer, 38 patients (4.3%) had a family history of bladder cancer in a first-degree relative. No significant association of age of diagnosis was observed between patients with and without a first-degree family history of bladder cancer (P = .3). In the second cohort, 27 of 80 (34%) patients with bladder cancer evaluated for cancer predisposition syndromes harbored a P/LP germline variant. P/LP variants were identified most commonly in the following genes: BRCA1 (n = 5), MSH2 (n = 5), MLH1 (n = 4), ATM (n = 3), and CHEK2 (n = 2). Of the 27 patients with identified germline P/LP variants, 20 (74%) had a family history of a tumor component syndrome in a first- or second-degree relative and 3 were subsequently diagnosed with another genetically-linked associated cancer.

CONCLUSION: Familial bladder cancer defined as bladder cancer in the proband and a first-degree relative, was present in 4.3% of patients with bladder cancer and was not associated with age of diagnosis. Additionally, among patients suspected to have a familial cancer syndrome, one-third harbored a germline P/LP variant. Further study of germline variants in patients with familial bladder cancer including somatic testing for loss of heterozygosity may provide insights regarding disease pathogenesis and inform therapy.

Alternate JournalClin Genitourin Cancer
PubMed ID36127252
Related Faculty: 
Pier Nuzzo, Ph.D.

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