Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer
Authors: Darst Burcu F. , Saunders Ed , Dadaev Tokhir , Sheng Xin , Wan Peggy , Pooler Loreall , Xia Lucy Y. , Chanock Stephen , Berndt Sonja I. , Wang Ying , Patel Alpa V. , Albanes Demetrius , Weinstein Stephanie J. , Gnanapragasam Vincent , Huff Chad , Couch Fergus J. , Wolk Alicja , Giles Graham G. , Nguyen-Dumont Tu , Milne Roger L. , Pomerantz Mark M. , Schmidt Julie A. , Travis Ruth C. , Key Timothy J. , Stopsack Konrad H. , Mucci Lorelei A. , Catalona William J. , Marosy Beth , Hetrick Kurt N. , Doheny Kimberly F. , MacInnis Robert J. , Southey Melissa C. , Eeles Rosalind A. , Wiklund Fredrik , Conti David V. , Kote-Jarai Zsofia , Haiman Christopher A. 
Published: September 2023

ImportanceGermline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease.ObjectiveTo identify genes associated with aggressive PCa.Design, Setting, and ParticipantsA 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa.ExposureSequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels.Main Outcomes and MeasuresThe primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa.ResultsA total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM (P ≤ 1.9 × 10−6), followed by NBN (P = 1.7 × 10−4). This study found nominal evidence (P &amp;lt; .05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53, RAD51D, BARD1, GEN1, and SLX4. Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa.Conclusions and RelevanceThe findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.