The risk ratio of prostate cancer was 4.6 (1.9-8.8) in first-degree relatives and 2.5 (1.2-4.6) in second-degree relatives of the 16 BRCA2 positive breast cancer probands.
In this commentary, we review the current literature and hypotheses surrounding the relationship between BRCA2 mutations and susceptibility to prostate cancer and speculate on the potential for involvement of additional genes.
Although BRCA2 is probably responsible only for a very small fraction of hereditary prostate cancers, this finding supports previous reports of an increased risk of prostate cancer in BRCA2 mutation carriers.
We report here an evaluation of the impact on relatives of being informed of study results that detected pathogenic BRCA2 mutations in a male relative, now deceased, who had early onset (under the age of 55) prostate cancer.
Decreased frequency and intensity of nuclear BRCA2 labeling were inversely correlated with Skp2 expression in high-grade prostatic intraepithelial neoplasia and PCa.
Molecular testing determined that his t-NEPC tumor (but not his original adenocarcinoma) harbored complete copy number loss of BRCA2, as well as copy number loss of another HR gene - ataxia telangiectasia, mutated (ATM).
Here, we report the frequency of the 999del5BRCA2 mutation in an Icelandic control population and four different groups of cancer patients diagnosed with (a) breast cancer; (b) ovarian cancer; (c) prostate cancer (patients younger than 65 years); and (d) other cancer types.
Germline breast cancer 1 gene (BRCA1) and breast cancer 2 gene (BRCA2) mutations are implicated in the highest risk of prostate cancer (PC) predisposition and aggressiveness.
Moreover, BRCA2-mutant tumours commonly show the concurrent presence of the intraductal carcinoma of the prostate (IDCP) pathology, a poor prognostic indicator.
Association with PCa risk was statistically significant for variants in BRCA2 (P < 0.001, OR = 5.65, 95% CI = 3.55-9.32), HOXB13 (P < 0.001, OR = 4.73, 95% CI = 2.84-8.19), and ATM (P < 0.001, OR = 2.86, 95% CI = 1.63-5.15).
We report 8 additional genes with suggestive evidence of association, including the DNA repair genes PARP2 and MSH6 Finally, we observed an excess of rare truncation variants in 5 genes, including the DNA repair genes MSH6, BRCA1, and BRCA2 This adds to the growing body of evidence that DNA repair pathway defects may influence susceptibility to aggressive prostate cancer.
In addition, it was recently shown that aberrations in DNA repair genes, such as BRCA2 and ATM, are present in both somatic and germline form in a significant minority of prostate cancer; these abnormalities can be targeted by drugs such as platinums and PARP inhibitors.