Abstract 688: Multi-stage exome sequencing study of 17,546 aggressive and non-aggressive prostate cancer cases
Authors: Darst Burcu F. , Saunders Ed , Dadaev Tokhir , Sheng Xin , Wan Peggy , Pooler Loreall , Xia Lucy Y. , Chanock Stephen , Berndt Sonja I. , Gapstur Susan M. , Stevens Victoria , Albanes Demetrius , Weinstein Stephanie J. , Gnanapragasam Vincent , 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 , Kote-Jarai Zsofia , Conti David V. , Haiman Christopher A. 
Published: June 2022

Rare pathogenic variants in DNA repair genes have been found to influence risk of aggressive prostate cancer. We conducted a large case-only exome sequencing study to further understand the role of rare coding variation in aggressive prostate cancer in a study of 9,185 aggressive (prostate cancer death, metastatic disease, T4, or both T3 and Gleason≥8) and 8,361 non-aggressive cases (T1/T2 and Gleason≤6) of European ancestry from 19 international studies. Stage 1 samples (N=5,545) had whole exome-sequencing, and stage 2 samples (N=12,001) had targeted exome sequencing for 1,459 genes selected based on stage 1 results and previous evidence. Logistic regression models were used to evaluate gene-based tests and the aggregate effect of multiple genes to investigate whether carrying pathogenic/likely pathogenic/deleterious (P/LP/D) variants (18,759 identified) was associated with risk of aggressive prostate cancer, prostate cancer death (N=6,033), or metastatic disease (N=1,730) compared to non-aggressive disease. Gene-based tests were meta-analyzed across stages 1 and 2. BRCA2, ATM, and NBN had the most statistically significant gene-based results: BRCA2 P/LP/D variant carriers had 4.3-fold higher odds of aggressive disease (95% CI=3.15-5.86, P=4x10-20), 4.7-fold higher odds of prostate cancer death (95% CI=3.41-6.59, P=2x10-20), and 5.7-fold higher odds of metastatic disease (95% CI=3.71-8.76, P=2x10-15); ATM P/LP/D variant carriers had 2.2-fold higher odds of aggressive disease (95% CI=1.58-2.99, P=2x10-6), 2.2-fold higher odds of prostate cancer death (95% CI=1.52-3.05, P=2x10-5), and 3.0-fold higher odds of metastatic disease (95% CI=1.93-4.61, P=9x10-7); and NBN P/LP/D variant carriers had 5.9-fold higher odds of metastatic disease (95% CI=2.56-13.84, P=3x10-5). Among potentially novel genes with strong but not exome-wide significant statistical evidence were MMP19, involved in reproduction and metastasis, with carriers having 2.8-fold higher odds of prostate cancer death (95% CI=1.53-5.05, P=8x10-4); PKD2L2, involved in fertility, with carriers having 3.5-fold higher odds of prostate cancer death (95% CI=1.76-7.04, P=5x10-4); and SMPD1, involved in converting sphingomyelin to ceramide, with carriers having 5.3-fold higher odds of metastatic disease (95% CI=1.85-14.98, P=0.002). At least one P/LP/D variant within a subset of 24 previously curated candidate prostate cancer DNA repair genes was carried by 12.8% of aggressive cases (OR=1.48, 95% CI=1.34-1.64, P=3x10-14), 12.6% of cases who died due to prostate cancer (OR=1.47, 95% CI=1.31-1.65, P=3x10-11), and 15.1% of metastatic cases (OR=2.16, 95% CI=1.57-2.16, P=5x10-14) compared to 9.4% of non-aggressive cases. These findings support the importance of rare genetic variation in aggressive prostate cancer risk and may have important implications for prostate cancer risk stratification and screening.

Citation Format: Burcu F. Darst, Ed Saunders, Tokhir Dadaev, Xin Sheng, Peggy Wan, Loreall Pooler, Lucy Y. Xia, Stephen Chanock, Sonja I. Berndt, Susan M. Gapstur, Victoria Stevens, Demetrius Albanes, Stephanie J. Weinstein, Vincent Gnanapragasam, Graham G. Giles, Tu Nguyen-Dumont, Roger L. Milne, Mark M. Pomerantz, Julie A. Schmidt, Ruth C. Travis, Timothy J. Key, Konrad H. Stopsack, Lorelei A. Mucci, William J. Catalona, Beth Marosy, Kurt N. Hetrick, Kimberly F. Doheny, Robert J. MacInnis, Melissa C. Southey, Rosalind A. Eeles, Fredrik Wiklund, Zsofia Kote-Jarai, David V. Conti, Christopher A. Haiman. Multi-stage exome sequencing study of 17,546 aggressive and non-aggressive prostate cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 688.