TY - JOUR
T1 - Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer
AU - Wu, Yishuo
AU - Yu, Hongjie
AU - Li, Shuwei
AU - Wiley, Kathleen
AU - Zheng, S. Lilly
AU - LaDuca, Holly
AU - Gielzak, Marta
AU - Na, Rong
AU - Sarver, Brice A.J.
AU - Helfand, Brian T.
AU - Walsh, Patrick C.
AU - Lotan, Tamara L.
AU - Cooney, Kathleen A.
AU - Black, Mary Helen
AU - Xu, Jianfeng
AU - Isaacs, William B.
N1 - Publisher Copyright:
Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - BACKGROUND: Rare germline mutations in several genes, primarily DNA repair genes, have been proposed to predict worse prognosis of prostate cancer (PCa). OBJECTIVE: To compare the frequency of germline pathogenic mutations in commonly assayed PCa genes between high- and low-grade PCa in patients initially presenting with clinically localized disease. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case-case study of 1694 PCa patients who underwent radical prostatectomy at Johns Hopkins Hospital, including 706 patients with high-grade (grade group [GG] 4 and GG5) and 988 patients with low-grade (GG1) disease. Germline DNA was sequenced for 13 candidate PCa genes using a targeted next-generation sequencing assay by Ambry Genetics. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Carrier rates of pathogenic mutations were compared between high- and low-grade PCa patients using the Fisher's exact test. RESULTS AND LIMITATIONS: Overall, the carrier rate of germline pathogenic mutations in the 13 genes was significantly higher in high-grade patients (8.64%) than in low-grade patients (3.54%, p = 9.98 × 10-6). Individually, significantly higher carrier rates for patients with high- versus low-grade PCa were found for three genes: ATM (2.12% and 0.20%, respectively, p = 9.35 × 10-5), BRCA2 (2.55% and 0.20%, respectively, p = 8.99 × 10-6), and MSH2 (0.57% and 0%, respectively, p = 0.03). The mutation carrier rate was significantly higher in patients with GG5 than in patients with GG1 disease for the 13 genes overall (13.07% and 3.54%, respectively, p = 1.27 × 10-9); for the three genes ATM, BRCA2, and MSH2 (7.73% and 0.40%, respectively, p = 3.20 × 10-13); and for the remaining nine DNA repair genes (5.07% and 2.43%, respectively, p = 0.02). CONCLUSIONS: In men undergoing treatment for clinically localized disease, pathogenic mutations in 13 commonly assayed genes, especially ATM, BRCA2, and MSH2, are most strongly associated with GG5 PCa. These findings emphasize the importance of genetic testing in men with high-grade PCa, particularly GG5 disease, to inform both treatment decisions and familial risk assessment. PATIENT SUMMARY: Prostate cancer in men with inherited mutations in 13 commonly assayed susceptibility genes is more likely to be high-grade, high-risk disease.
AB - BACKGROUND: Rare germline mutations in several genes, primarily DNA repair genes, have been proposed to predict worse prognosis of prostate cancer (PCa). OBJECTIVE: To compare the frequency of germline pathogenic mutations in commonly assayed PCa genes between high- and low-grade PCa in patients initially presenting with clinically localized disease. DESIGN, SETTING, AND PARTICIPANTS: A retrospective case-case study of 1694 PCa patients who underwent radical prostatectomy at Johns Hopkins Hospital, including 706 patients with high-grade (grade group [GG] 4 and GG5) and 988 patients with low-grade (GG1) disease. Germline DNA was sequenced for 13 candidate PCa genes using a targeted next-generation sequencing assay by Ambry Genetics. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Carrier rates of pathogenic mutations were compared between high- and low-grade PCa patients using the Fisher's exact test. RESULTS AND LIMITATIONS: Overall, the carrier rate of germline pathogenic mutations in the 13 genes was significantly higher in high-grade patients (8.64%) than in low-grade patients (3.54%, p = 9.98 × 10-6). Individually, significantly higher carrier rates for patients with high- versus low-grade PCa were found for three genes: ATM (2.12% and 0.20%, respectively, p = 9.35 × 10-5), BRCA2 (2.55% and 0.20%, respectively, p = 8.99 × 10-6), and MSH2 (0.57% and 0%, respectively, p = 0.03). The mutation carrier rate was significantly higher in patients with GG5 than in patients with GG1 disease for the 13 genes overall (13.07% and 3.54%, respectively, p = 1.27 × 10-9); for the three genes ATM, BRCA2, and MSH2 (7.73% and 0.40%, respectively, p = 3.20 × 10-13); and for the remaining nine DNA repair genes (5.07% and 2.43%, respectively, p = 0.02). CONCLUSIONS: In men undergoing treatment for clinically localized disease, pathogenic mutations in 13 commonly assayed genes, especially ATM, BRCA2, and MSH2, are most strongly associated with GG5 PCa. These findings emphasize the importance of genetic testing in men with high-grade PCa, particularly GG5 disease, to inform both treatment decisions and familial risk assessment. PATIENT SUMMARY: Prostate cancer in men with inherited mutations in 13 commonly assayed susceptibility genes is more likely to be high-grade, high-risk disease.
KW - DNA repair genes
KW - Germline
KW - High grade
KW - Mutation
KW - Prostate cancer
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UR - http://www.scopus.com/inward/citedby.url?scp=85084026465&partnerID=8YFLogxK
U2 - 10.1016/j.euo.2019.12.003
DO - 10.1016/j.euo.2019.12.003
M3 - Article
C2 - 31948886
AN - SCOPUS:85084026465
SN - 2588-9311
VL - 3
SP - 224
EP - 230
JO - European Urology Oncology
JF - European Urology Oncology
IS - 2
ER -