What question did this study set out to answer?

This research aims to evaluate the roles of common and rare genetic variants in prostate cancer risk among diverse populations.

April 19, 2026

Abstract LB390: Genetic risk of prostate cancer: Insights from the Prostate Cancer Sequencing Consortium

Key Result

Rare germline pathogenic variants in eight genes, notably HOXB13 (OR=3.7), SMOC2 (OR=3.2), and BRCA2 (OR=2.0), were significantly associated with increased prostate cancer risk.

Key Points

This research aims to evaluate the roles of common and rare genetic variants in prostate cancer risk among diverse populations.
Analyzed whole-exome sequencing data from 427,388 males, including 51,452 prostate cancer cases and 375,936 controls.
Conducted single-variant association analyses for variants on chromosomes 1-22 and X with a minor allele count ≥ 5.
Performed gene-based analyses looking at pathogenic variants and gene associations using logistic regression and meta-analysis.
Identified 496 variants that reached genome-wide significance, with 458 linked to known prostate cancer risk regions.
Eight genes showed significant associations for prostate cancer susceptibility, including HOXB13 and BRCA2, with odds ratios indicating increased risk.
Results suggest a strong role of rare germline pathogenic variants in prostate cancer susceptibility and highlight the need for further research.

Structured PICO

Do common and rare germline pathogenic variants increase the risk of prostate cancer in male participants?

Population

427,388 male participants (51,452 prostate cancer cases and 375,936 controls) from ten biobanks and studies, comprising approximately 79% European, 18% African, and 3% other ancestry populations.

Intervention

Presence of common genetic variants and rare germline pathogenic variants (PVs)

Comparator

Absence of variants / controls without prostate cancer

Outcome

Overall prostate cancer risk

Rare germline pathogenic variants, particularly in cancer predisposition and DNA repair genes, are significantly associated with increased prostate cancer susceptibility.

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Abstract Inherited susceptibility plays a critical role in prostate cancer (PCa) risk. Using large biobank and case-control datasets, we evaluated the contribution of both common variants and rare germline pathogenic variants (PVs) to overall PCa risk. The Prostate Cancer Exome Sequencing Consortium currently includes 427, 388 male participants (51, 452 PCa cases and 375, 936 controls) with whole-exome sequencing data from ten biobanks and studies: UK Biobank (14, 669 cases/195, 600 controls), All of Us Research Program (7, 577/75, 226), African Ancestry Prostate Cancer Consortium (7, 176/4, 675), Mayo Clinic Biobank (6, 031/15, 084), Mass General Brigham Biobank (3, 393/14, 095), Geisinger’s MyCode Community Health Initiative (3, 026/15, 130), UCLA ATLAS Precision Medicine Biobank (2, 850/16, 904), Penn Medicine Biobank (2, 598/16, 255), Colorado Center for Personalized Medicine (2, 269/13, 399), and Malmo Diet and Cancer (1, 863/9, 568). Based on self-reported race/ethnicity and estimated genetic ancestry, the cases comprise approximately 79% European, 18% African, and 3% other ancestry populations. Single-variant association analyses tested all variants on chromosomes 1-22 and X with a minor allele count ≥ 5. In gene-based analyses, PVs were defined as rare variants (minor allele frequency MAF 1% in controls) that had either a Variant Effect Predictor (VEP) impact score of “high” or a pathogenic or likely pathogenic ClinVar classification. Associations were estimated using Firth logistic regression, adjusting for age and the top ten genetic principal components. Results from individual studies were combined using fixed-effect meta-analysis. In single-variant association analyses, 496 variants reached genome-wide significance (p5×10-8; MAF0. 02%). Among these, 458 (92%) variants mapped to previously known risk regions, including three rare PVs in HOXB13 (rs138213197), CHEK2 (rs555607708), and FAM111A (rs533676902). Characterization of the remaining 38 variants is ongoing. Gene-based analyses identified significant associations (p2. 4×10-6) for eight genes: HOXB13 (OR=3. 7, 95% CI=3. 3-4. 2), BRCA2 (OR=2. 0, 95% CI=1. 7-2. 3), CHEK2 (OR=1. 6, 95% CI=1. 5-1. 8), ATM (OR=1. 6, 95% CI=1. 4-1. 9), FAM111A (OR=1. 4, 95% CI=1. 3-1. 5), BIK (OR=1. 4, 95% CI=1. 2-1. 6), SAMHD1 (OR=2. 1, 95% CI=1. 6-2. 7), and SMOC2 (OR=3. 2, 95% CI=2. 0-5. 1). All genes except SMOC2 have been previously implicated in PCa susceptibility. Among cancer predisposition and DNA repair genes, nominal associations were also observed for XRCC2 (OR=1. 6, 95% CIs=1. 2-2. 3) and BRCA1 (OR=1. 2, 95% CI=1. 0-1. 4), whereas the association was not significant for PALB2 (OR=1. 2, 95% CI=0. 9-1. 5). These findings reinforce the role of rare germline PVs, particularly in cancer predisposition and DNA repair genes, in PCa susceptibility. As additional studies are incorporated into the Consortium, we expect this work to provide a more comprehensive characterization of the genetic architecture of PCa. Citation Format: Yifan Zhang, Shuyan Cheng, Nicholas Boddicker, Matthew Lebo, Alexander S. Berry, Roni Haas, Ryan Hausler, Tokhir Dadaev, Heena Desai, Alex A. Rodriguez, Ravi K. Madduri, Andrew Hill, Xin Sheng, Susan M. Gundell, Mine Cicek, Penn Medicine Biobank, Olle Melander, Chris R. Gignoux, Isla P. Garraway, Bogdan Pasaniuc, Paul C. Boutros, Matt Oetjens, Adam S. Kibel, Robert J. Klein, Zsofia Kote-Jarai, Fergus J. Couch, Kara N. Maxwell, Burcu F. Darst, David V. Conti, Christopher A. Haiman, Fei Chen. Genetic risk of prostate cancer: Insights from the Prostate Cancer Sequencing Consortium abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB390.

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