TY - JOUR
T1 - Inherited Germline Cancer Susceptibility Gene Variants in Individuals with Non-Muscle-Invasive Bladder Cancer
AU - Pietzak, Eugene J.
AU - Whiting, Karissa
AU - Srinivasan, Preethi
AU - Bandlamudi, Chaitanya
AU - Khurram, Aliya
AU - Joseph, Vijai
AU - Walasek, Aleksandra
AU - Bochner, Emily
AU - Clinton, Timothy
AU - Almassi, Nima
AU - Truong, Hong
AU - de Jesus Escano, Manuel R.
AU - Wiseman, Michal
AU - Mandelker, Diana
AU - Kemel, Yelena
AU - Zhang, Liying
AU - Walsh, Michael F.
AU - Cadoo, Karen A.
AU - Coleman, Jonathan A.
AU - Al-Ahmadie, Hikmat
AU - Rosenberg, Jonathan E.
AU - Iyer, Gopakumar V.
AU - Solit, David B.
AU - Ostrovnaya, Irina
AU - Offit, Kenneth
AU - Robson, Mark E.
AU - Stadler, Zsofia K.
AU - Berger, Michael F.
AU - Bajorin, Dean F.
AU - Carlo, Maria
AU - Bochner, Bernard H.
N1 - Publisher Copyright:
© 2022 TheAuthors.
PY - 2022/10/1
Y1 - 2022/10/1
N2 - Purpose: Identification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non-muscle-invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is understudied. Experimental Design: Germline analysis was conducted on paired tumor/normal sequencing results from two distinct cohorts of patients initially diagnosed with NMIBC. Associations between clinicopathologic features and clinical outcomes with the presence of P/LP germline variants in ≥76 hereditary cancer predisposition genes were analyzed. Results: A similar frequency of P/LP germline variants were seen in our two NMIBC cohorts [12% (12/99) vs. 8.7% (10/115), P = 0.4]. In the combined analysis, P/LP germline variants were found only in patients with high-grade NMIBC (22/163), but none of the 46 patients with low-grade NMIBC (13.5% vs. 0%, P = 0.005). Fifteen (9.2%) patients with high-grade NMIBC had P/ LP variants in DNA damage response genes, most within the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways. Contrary to prior reports in patients with NMIBC not receiving Bacillus Calmette-Guerin (BCG), P/LP germline variants were not associated with worse recurrence-free or progression-free survival in patients treated with BCG or with risk of developing upper tract urothelial carcinoma. Conclusions: Our results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of initial tumor stage. Therapeutic strategies that target impairedDNArepair may benefit patients with high-grade NMIBC.
AB - Purpose: Identification of inherited germline variants can guide personalized cancer screening, prevention, and treatment. Pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes are frequent among patients with locally advanced or metastatic urothelial carcinoma, but their prevalence and significance in patients with non-muscle-invasive bladder cancer (NMIBC), the most common form of urothelial carcinoma, is understudied. Experimental Design: Germline analysis was conducted on paired tumor/normal sequencing results from two distinct cohorts of patients initially diagnosed with NMIBC. Associations between clinicopathologic features and clinical outcomes with the presence of P/LP germline variants in ≥76 hereditary cancer predisposition genes were analyzed. Results: A similar frequency of P/LP germline variants were seen in our two NMIBC cohorts [12% (12/99) vs. 8.7% (10/115), P = 0.4]. In the combined analysis, P/LP germline variants were found only in patients with high-grade NMIBC (22/163), but none of the 46 patients with low-grade NMIBC (13.5% vs. 0%, P = 0.005). Fifteen (9.2%) patients with high-grade NMIBC had P/ LP variants in DNA damage response genes, most within the nucleotide excision repair (ERCC2/3) and homologous recombination repair (BRCA1, NBN, RAD50) pathways. Contrary to prior reports in patients with NMIBC not receiving Bacillus Calmette-Guerin (BCG), P/LP germline variants were not associated with worse recurrence-free or progression-free survival in patients treated with BCG or with risk of developing upper tract urothelial carcinoma. Conclusions: Our results support offering germline counseling and testing for all patients with high-grade bladder cancer, regardless of initial tumor stage. Therapeutic strategies that target impairedDNArepair may benefit patients with high-grade NMIBC.
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U2 - 10.1158/1078-0432.CCR-22-1006
DO - 10.1158/1078-0432.CCR-22-1006
M3 - Article
C2 - 35833951
AN - SCOPUS:85138142194
SN - 1078-0432
VL - 28
SP - 4267
EP - 4277
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 19
ER -