Germline Variants and Risk of Aggressive Prostate Cancer

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In a study reported in JAMA Oncology, Darst et al identified germline genetic variants that were associated with increased risk of aggressive vs nonaggressive prostate cancer.

As stated by the investigators, “Germline gene panel testing is recommended for men with advanced prostate cancer 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 prostate cancer risk and aggressive disease.”

Study Details

The study included 17,546 men of European ancestry from 18 international studies. Sequencing data were evaluated exome-wide and in investigation of 29 DNA repair pathway and cancer susceptibility genes (many of which currently are included on gene panels). Associations were sought for aggressive prostate cancer (category T4 or both T3 and Gleason score ≥ 8 tumors, metastatic prostate cancer, or prostate cancer death) vs nonaggressive prostate cancer (category T1 or T2 and Gleason score ≤ 6 tumors without known recurrence) and for metastatic vs nonaggressive prostate cancer.

Key Findings

The cohort included 9,185 men with aggressive prostate cancer (including 6,033 who died of prostate cancer and 2,397 with metastasis) and 8,361 with nonaggressive prostate cancer. Mean age at diagnosis was 65.1 vs 63.7 years.

The most highly significant associations with aggressive or metastatic disease were found for deleterious variants in known prostate cancer risk genes BRCA2 and ATM, followed by NBN. Carrier frequency of deleterious BRCA2 alleles was 2.4% in aggressive cases (odds ratio [OR] = 4.29, 95% confidence interval [CI] = 3.15–5.86, P = 4.0 × 10−20) and 3.0% in metastatic cases (OR = 5.61, 95% CI = 3.73–8.44, P = 1.3 × 10−16) compared with 0.7% in nonaggressive cases. Carrier frequency of deleterious ATM alleles was 1.6% in aggressive cases (OR = 2.17, 95% CI = 1.58–2.99, P = 1.6 × 10−6) and 1.9% in metastatic cases (OR = 2.80, 95% CI = 1.83–4.29, P = 1.9 × 10−6) vs 0.7% in nonaggressive cases. Carrier frequency for deleterious NBN alleles was 0.5% in metastatic cases (OR = 5.16, 95% CI = 2.19–12.12, P = 1.7 × 10−4) compared with 0.2% in nonaggressive cases.

Less significant associations with aggressive or metastatic disease were found for deleterious variants in MSH2 (OR for aggressive disease = 3.27, 95% CI = 1.29–8.31, P = .01), XRCC2 (OR for aggressive disease = 6.24, 95% CI = 1.24–31.4, P = .03), and MRE11A (OR for metastatic disease = 4.70, 95% CI = 1.39–15.90, P = .01). Variants in five additional genes had odds ratios of ≥ 2.0 for aggressive disease—TP53, RAD51D, BARD1, GEN1, and SLX4—that were not statistically significant vs nonaggressive disease.

Overall, deleterious variants in the 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic prostate cancer.

The investigators concluded, “The findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with prostate cancer and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.”

Christopher A. Haiman, ScD, of the Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, and Burcu F. Darst, PhD, of the Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, are the corresponding authors for the JAMA Oncology article.

Disclosure: The study was supported by the National Cancer Institute and others. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.