Abstract 1896: Simple mediation analysis to determine if MSMB is a prostate specific antigen (PSA) or prostate cancer (PC) gene

Abstract

Abstract Background: PC genome-wide association studies have identified MSMB as a candidate susceptibility gene in European populations screened and unscreened for PC. Studies have also shown an association between MSMB (rs10993994) and PSA levels in men without PC diagnoses, suggesting that the association between MSMB and PC may be a reflection of disease screening with PSA. The goal of this study was to determine whether MSMB is a prostate cancer gene or a PSA gene by testing the hypothesis that PSA at diagnosis mediates the relationship between MSMB and PC risk and severity in European Americans. Methods: Using 772 PC cases and 194 controls from our clinic-based case-control study, we conducted a simple mediation analysis using 4 Steps and the Sobel test. In step 1 we tested the significance of MSMB(rs10993994) on PC risk and severity. We then tested the significance of MSMB and PSA at diagnosis (Step 2). In Step 3, tested whether there was a relationship between PSA and PC not accounted for by MSMB. Since Steps 2/3 were passed, we had evidence consistent with a nonzero indirect effect, leading to Step 4, where we compared the observed values and the significance of the relationship between MSMB and PC unadjusted (Step 1) and adjusted for PSA. A Sobel Test was then conducted to determine if the indirect effect of MSMB on PC risk and severity via PSA was significant. Results were stratified by prostate cancer severity: Aggressive prostate cancer (Tumor stage >II and/or Gleason >7); Nonaggressive prostate cancer (Tumor stage <II and/or Gleason <7). For Steps 1,3,4, odds ratios (OR) and 95% confidence intervals(95%CI) were calculated using unconditional logistic regression, adjusted by age. For Step 2, linear regression coefficients were calculated adjusted by age. Results: Step 1: MSMB was significantly associated with PC risk(OR=1.40,95%CI=1.02-1.93) and nonaggressive PC(OR=1.52,95%CI=1.08-2.16), particularly for the risk genotype(TT)(PC OR=1.91,95%CI=1.01-3.66; nonaggressive OR=2.27,95%CI=1.13-4.55). Step 2: MSMB, particularly the TT genotype, and LogPSA were significantly associated (p=0.04). Step 3: LogPSA was associated with PC risk (OR=13.1,95%CI=8.24-20.9) and nonaggressive PC(OR=8.47,95%CI=5.33-13.5), adjusting for MSMB. Step 4: The association between MSMB and PC risk(OR=1.37,95%CI=0.88-2.14; TT OR=1.66,95%CI=0.70-3.97) and nonaggressive PC(OR=1.47,95%CI=0.93-2.33; TT OR=1.98,95%CI=0.81-4.89) was lower and no longer significant after adjusting for LogPSA, suggesting that PSA is a complete mediator. The Sobel test showed the indirect effect of MSMB on PC (p=0.048) and nonaggressive PC(p=0.049) was significant. Discussion: Our results show that PSA screening is a mediator of the relationship between MSMB and PC risk and nonaggressive PC, suggesting that MSMB is more a PSA gene than a PC risk gene. Our study has limited power and would need to be validated in larger studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1896. doi:10.1158/1538-7445.AM2011-1896