ASCO GU 2021: Germline Alterations in Cancer Susceptibility Genes in Women with High-Risk Bladder Cancer: Implications for Germline Testing and Clinical Management

( While advanced bladder cancer has a generally poor prognosis, there are notable gender-based differences. While women have a lower incidence of bladder cancer, they are, in general, diagnosed with more advanced disease at presentation. Further, even when tumor stage and treatment approach are accounted for, women have worse outcomes. However, the basis of these discrepancies is, to date, unknown. To address this, in a poster presentation at the 2021 ASCO GU Cancers Symposium, Dr. Truong and colleagues sound to assess germline variants among women with bladder cancer which may explain their poor prognosis.

To do so, the authors utilized an institutional prospective matched tumor-normal tissue genomic profiling initiative. They then determined both the prevalence and spectrum of pathogenic/likely pathogenic germline variants among women with bladder cancer. To identify germline DNA mutations, ≥77 cancer susceptibility genes were tested using next-generation sequencing in 686 patients with bladder cancer with analysis stratified by gender. Mutation frequency and clinical characteristics were assessed by gender.


The authors examined a total of 686 patients with bladder cancer who underwent germline testing, 182 (26%) of whom were women and 512 (74%) of whom were men. The median age of the cohort at the time of diagnosis was 66 ± 11.3 and 65 ± 11.3 years for women and men, respectively. Notably, 22 women (12%) had bladder cancer diagnosis before age 50 years.

Rates of tobacco exposure (57% vs 63%, p = 0.1), family history of bladder cancer (10% vs 10%, p = 0.9), were similar between women and men. Disease stage at diagnosis (non-muscle invasive bladder cancer [NMIBC] 28% vs 35%, MIBC 29% vs 18%, and metastatic disease 43% vs 48%, p = 0.04) and variant (non-urothelial) histology (adenocarcinoma 5% vs. 1%; squamous cell carcinoma 1% vs 0.2%, p = 0.001) differed based on gender.

Further, pathogenic/likely pathogenic germline variants were found more frequently in women than men (37 [20%] vs. 68 [14%], p = 0.04). Further, 28 women (15%) had pathogenic/likely pathogenic variants in DNA-damage repair (DDR) genes, while 23 (13%) carried moderate/high penetrance germline mutations, including most commonly BRCA1/2, CHEK2, NBN, ATM, and MITF.


Importantly, current clinical guideline for referral for genetic testing failed to identify 12 (52%) women with moderate/high penetrance germline mutations. This is particularly notable as 9 women (5%) carried germline mutations associated with increased risk of ovarian/endometrial cancers (BRCA1/2 [5], ATM [2], MLH1 [1], TP53 [1]).

The authors conclude that pathogenic/likely pathogenic germline alterations are more common among women with bladder cancer, as compared to men. Some of these alterations are associated with tumors in other organs which may be suitable for screening or risk-reducing surgery, as well as familial counselling.

Presented by: Hong Truong, MD, MS, Memorial Sloan Kettering Cancer Center, New York, NY

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter during the 2021 ASCO Genitourinary Cancers Symposium (ASCO GU), February 11th to 13th, 2021
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