Presentation Authors: Melissa J. Huynh*, Kathryn L. Penney, Chirag Vyas, Adam S. Kibel, Boston, MA
Introduction: The need to differentiate patients at risk for developing aggressive prostate cancer (CaP) from those at risk for less aggressive disease has led to efforts to identify genetic markers to predict disease course and personalize treatment. Prior work from our group identified 13 single nucleotide polymorphisms (SNPs) in 12 cell cycle genes that were associated with risk of aggressive CaP. We sought to replicate those results in the European-American population of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.
Methods: We focused on variants associated with aggressive CaP in the prior cohort, which included 13 SNPs in 12 genes (CCNC, CCND3, CCNG1, CCNT2, CDK2, CDK6, MDM2, SKP2, TERF2, WEE1, YWHAB, YWHAH). Variants were genotyped using Pyrosequencing assay. Patients were classified into high risk (Gleasonâ‰¥8, pT3b, N+, M+), low risk (Gleasonâ‰¤7, â‰¤pT3a, N0, M0) or non-cancer control groups based on clinicopathologic characteristics. Logistic regression analysis was used to compare genotype frequencies of each variant between groups using the dominant model.
Results: There were 108 aggressive and 1080 non-aggressive CaP patients, and 1155 controls. CDK6 (rs8) was associated with increased risk of any CaP (OR 1.2, 95% CI 1.02-1.42; p=0.032) and high risk disease (OR 1.63, 95% CI 1.09-2.42; p=0.017) vs. controls. This was in contrast to the prior study where the CDK6 variants were protective against aggressive CaP . CCNG1 (rs11541970) approached significance (OR 1.86, 95% CI 0.99-3.46; p=0.052) between high risk and control groups, but its effect was also opposite in direction compared to the previous study. CCNC (rs330812) conferred a protective effect consistent with the prior study, but did not reach statistical significance (OR 0.69, 95% CI 0.44-1.07; p=0.101). No associations with any cell cycle gene variants were detected when comparing high and low risk patients.
Conclusions: Our study did not replicate our prior results. CDK6 predicted increased risk of developing any CaP and high risk CaP. However, directionality was opposite to the prior study, indicating that this variant is unlikely to be a true predictor of increased risk of or protection from aggressive CaP. CCNC demonstrated a protective effect in both studies, but did not reach statistical significance in our analysis. Nonetheless, further work to explore its role in predicting risk of aggressive disease is warranted given the absence of validated SNPs in the identification of aggressive CaP._x000D_
(Reference: Kibel, A. S. et al (2016.) Prostate, 76: 479-90.)
Source of Funding: NCI R01 grant No. CA112028