Associations Between Polymorphisms in Genes Related to Oxidative Stress and DNA Repair, Interactions With Serum Antioxidants, and Prostate Cancer Risk: Results From the Prostate Cancer Prevention Trial

Study of polymorphisms in genes related to the generation and removal of oxidative stress and repair of oxidative DNA damage will lead to new insights into the genetic basis of prostate cancer. In the Prostate Cancer Prevention Trial (PCPT), a double-blind, randomized controlled trial testing finasteride versus placebo for prostate cancer prevention, we intend to investigate the role of oxidative stress/DNA repair mechanisms in prostate cancer etiology and whether these polymorphisms modify prostate cancer risk by interacting with antioxidant status in both placebo and finasteride arms. We evaluated associations of selected candidate polymorphisms in genes in these pathways, and interactions with pre-diagnostic serum antioxidants, and the risk of prostate cancer among 1,598 cases and 1,706 frequency-matched controls enrolled in the PCPT. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable-adjusted logistic regression models. While there were no statistically significant associations observed in the placebo arm, several SNPs were associated with prostate cancer in the finasteride arm. Specifically, APEX1-rs1760944 was associated with increased risk of total prostate cancer (per minor allele: p-trend=0.04). OGG1-rs1052133 was positively (CG/GG vs. CC: OR=1.32, 95% CI: 1.01-1.73) and NOS3-rs1799983 was inversely (per minor allele: p-trend=0.04) associated with risk of low-grade prostate cancer. LIG3-rs1052536 and XRCC1-rs25489 were suggestively associated with reduced risk of high-grade prostate cancer (per minor allele: both p-trend=0.04). In the placebo arm, significant associations were observed among men with higher serum lycopene for APEX1-rs1760944 and NQO1-rs1800566, or higher serum β-cryptoxanthin for ERCC4-rs1800067. In the finasteride arm, stronger associations were observed among men with lower serum lycopene for NOS3-rs1799983, higher serum α-carotene, β-carotene, and β-cryptoxanthin for LIG3-rs1052536, or lower serum retinol for SOD2-rs1799725. These results suggest that germline variations in oxidative stress and DNA repair pathways may contribute to prostate carcinogenesis and that these associations may differ by intraprostatic sex steroid hormone status and be further modified by antioxidant status. Findings provide insights into the complex role of gene, gene-antioxidant and -finasteride interactions in prostate cancer etiology, and thus may lead to the development of preventative strategies.

Physician Attitudes and Self-reported Practices Toward Prostate Cancer Screening in Black and White Men

Background and Objectives: Updated 2018 prostate cancer screening guidelines recommend informed decision-making discussions, which should include education on prostate cancer’s disproportionate impact on Black men. It is unknown whether academic family physicians follow these guidelines. Methods: Family physicians were surveyed as part of the 2020 Council of Academic Family Medicine Educational Research Alliance (CERA) survey. We used χ2 to compare physicians’ knowledge and screening practices stratified by physician age, gender, and percentage of Black patients in patient panel. We calculated logistic regressions predicting shared decision-making conversations, barriers to shared decision-making, inclusion of race in prostate cancer screening approach, and prostate-specific antigen (PSA) testing adjusted for physician age, gender, and percentage of Black patients. Results: Physicians reported engaging in shared decision-making for prostate cancer screening in half of eligible men. Only 29.2% of physicians reported routinely informing Black men of their increased prostate cancer risk. In logistic regressions, physician gender (female) and fewer Black patients in panel (<25%) were associated with lower frequency of shared decision-making with Black patients. Physician age (<40 years) was associated with not discussing race during screening discussions (OR 2.24, 95% CI 1.55–3.23). Conclusions: Most academic family physicians do not appropriately inform Black men of increased prostate cancer risk, with younger physicians less likely to discuss race than older physicians. Female physicians, and physicians who see fewer Black patients, are less likely to have shared decision-making conversations with Black patients. This suggests educational efforts for these groups are needed to address health disparities in prostate cancer.

BRCA1 and BRCA2 pathogenic variants and prostate cancer risk: systematic review and meta-analysis

Background BRCA1 and BRCA2 pathogenic variants (PVs) are associated with prostate cancer (PCa) risk, but a wide range of relative risks (RRs) has been reported. Methods We systematically searched PubMed, Embase, MEDLINE and Cochrane Library in June 2021 for studies that estimated PCa RRs for male BRCA1/2 carriers, with no time or language restrictions. The literature search identified 27 studies (BRCA1: n = 20, BRCA2: n = 21). Results The heterogeneity between the published estimates was high (BRCA1: I2 = 30%, BRCA2: I2 = 83%); this could partly be explained by selection for age, family history or aggressive disease, and study-level differences in ethnicity composition, use of historical controls, and location of PVs within BRCA2. The pooled RRs were 2.08 (95% CI 1.38–3.12) for Ashkenazi Jewish BRCA2 carriers, 4.35 (95% CI 3.50–5.41) for non-Ashkenazi European ancestry BRCA2 carriers, and 1.18 (95% CI 0.95–1.47) for BRCA1 carriers. At ages <65 years, the RRs were 7.14 (95% CI 5.33–9.56) for non-Ashkenazi European ancestry BRCA2 and 1.78 (95% CI 1.09–2.91) for BRCA1 carriers. Conclusions These PCa risk estimates will assist in guiding clinical management. The study-level subgroup analyses indicate that risks may be modified by age and ethnicity, and for BRCA2 carriers by PV location within the gene, which may guide future risk-estimation studies.