Series of Studies Identify Genetic Risk Factors for Prostate Cancer

The collective findings of a series of articles published in the journals European Urology, Journal of the National Cancer Institute, and International Journal of Cancer indicate that genetic alterations in the BRCA2, PALB2, and ATM genes are associated with prostate cancer risk in men that have a strong family history of prostate cancer and also increases their risk of an aggressive form of the disease.¹

“Our findings contribute important evidence to support the clinical interpretation of genetic variation and the identification of the men at greatest risk of developing the disease,” Tu Nguyen-Dumont, PhD, from the Monash School of Clinical Sciences based at Monash Health, said in a press release. “This new data will improve the care of men with and without prostate cancer, including the ability to predict susceptibility to aggressive prostate cancer and put in place measures to mitigate or even prevent the disease.”

In a study published in European Urology, researchers used a two-stage design to detect new genetic variants associated with prostate cancer.² In the first stage, whole-exome sequencing was used to identify potential risk alleles among men with prostate cancer who had a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Genes identified in stage 1 were then screened in stage 2 using a custom-capture design in an independent set of 2917 cases and 1899 controls.

Overall, 11 genes previously reported to be associated with prostate cancer were detected, including ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT, as well as an additional 10 novel genes, including PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3. Of the 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive prostate cancer.

Moreover, in a study published in the Journal of the National Cancer Institute, researchers evaluated 5545 men of European ancestry, including 2775 with non-aggressive and 2770 with aggressive prostate cancer, consisting of a total of 467 metastatic cases (16.9%).³ The samples used in the study were assembled from 12 international studies and germline sequenced together.

In this study, BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of non-aggressive cases carrying rare pathogenic, likely pathogenic, or deleterious (P/LP/D) BRCA2 alleles (OR = 3.19; 95% CI, 1.94 to 5.25; P = 8.58 x 10-7) and 0.65% of aggressive and 0.11% of non-aggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31; 95% CI, 1.83 to 21.68; P = 4.79 x 10-4). Further, ATM was found to have a nominal association, with 1.6% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D ATM alleles (OR = 1.88; 95% CI, 1.10 to 3.22; P = .02).

In aggregate, P/LP/D alleles within 24 literature-curated candidate prostate cancer DNA repair genes were also more common in aggressive than non-aggressive cases (carrier frequencies = 14.2% versus 10.6%, respectively; P = 5.56 x 10-5). However, this difference was revealed to be statistically non-significant (P = .18) after excluding BRCA2, PALB2, and ATM. Of the 24 literature-curated genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI, -1.65 to 0.48, P = 3.71 x 10-4).

Lastly, in a case-case study of prostate cancer published in the International Journal of Cancer, researchers compared the prevalence of germline pathogenic and likely pathogenic (P/LP) genetic variants among 787 men with aggressive disease and 769 with nonaggressive disease.⁴ Ultimately, P/LP variants were observed in 11.4% of men with aggressive prostate cancer and 9.8% of men with nonaggressive prostate cancer (two‐tailed Fisher's exact tests, P = .28).

In addition, the proportion of BRCA2 and ATM P/LP variant carriers in men with aggressive prostate cancer surpassed that observed in men with nonaggressive prostate cancer, with 2.3% carriers (18/787) and 0.5% carriers (4/769; P = .004), and 0.02% carriers (14/787) and 0.01% carriers (5/769; P = .06), respectively.

“Together these results provide important evidence upon which to further advance precision prevention for prostate cancer,” Melissa C. Southey, BSc, PhD, chair of Precision Medicine at Monash University and research director of the Monash Partners Comprehensive Cancer Consortium, said in the release.

As research in this area continues, the investigators suggested that the research reported herein provides important evidence which will be used to advance precision prevention for prostate cancer moving forward.

References:

1. Genetic risk factors identified for prostate cancer [news release]. Published October 12, 2020. Accessed October 26, 2020. https://www.monash.edu/medicine/news/latest/2020-articles/genetic-risk-factors-identified-for-prostate-cancer

2. Schaid DJ, McDonnell SK, FitzGerald LM, et al. Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer. European Urology. doi: 10.1016/j.eururo.2020.07.038

3. Darst BF, Dadaev T, Saunders E, et al. Germline sequencing DNA repair genes in 5,545 men with aggressive and non-aggressive prostate cancer. Journal of the National Cancer Institute. doi: 10.1093/jnci/djaa132

4. Nguyen-Dumont T, MacInnis RJ, Steen JA, et al. Rare germline genetic variants and risk of aggressive prostate cancer [news release]. International Journal of Cancer. doi: 10.1002/ijc.33024