Abstract 2832: Genetic variation in TGFB1 , TGFBR1 , TGFBR2 , and prostate cancer risk and recurrence

Background: The transforming growth factor-β (TGF-β) signaling pathway has been reported to play a dual role in prostate carcinogenesis. Initially, TGF-β signaling inhibits tumor growth by its antiproliferative activity, but eventually it promotes tumor development by enhancing tumor cell motility and metastasis. We investigated whether common genetic variation in TGFB1, TGFBR1, and TGFBR2 influences the risk of aggressive prostate cancer and biochemical recurrence. Methods: Forty-four tag SNPs in TGFB1, TGFBR1, and TGFBR2 were examined in a case-control study of aggressive prostate cancer (501 cases/538 controls) and a follow-up study of biochemical recurrence (824 cases). Aggressive disease was defined as having either having a Gleason score ≥7 or TNM stage ≥ T2c, or PSA at diagnosis >10 ng/ml. Biochemical recurrence was defined as post-treatment prostate specific antigen (PSA) levels >0.3 ng/ml for radical prostatectomy patients or 2 ng/ml increase above the nadir for radiotherpay patients. Odds ratios (OR) and 95% Confidence Intervals (CI) were estimated by unconditional logistic regression to evaluate the association between SNPs and aggressive prostate cancer risk. Hazard ratios (HR) and 95% CI were estimated by Cox proportional hazard regression to examine the association between SNPs and biochemical recurrence. Results: For risk of aggressive disease, three SNPs were nominally statistically significant (TGFB1-rs4803455; TGFBR1-rs10512263; TGFBR2-rs2276768) with the most compelling polymorphism (TGFBR1-rs10512263) having an OR=1.76; 95% CI: 1.14-2.43 (P = 0.008) per additional minor allele. For risk of biochemical recurrence, seven SNPs were nominally statistical significant (TGFBR1- rs10739778; TGFBR2- rs12493607, rs2082224, rs1346907, rs1431131, rs1835538, rs11129421) with TGFBR2- rs12493607 associated with a HR=1.40; 95% CI: 1.14-1.71; P=0.001 per additional minor allele. Conclusion: Our study suggests that genetic variation in the TGF-β pathway may be associated with risk of aggressive prostate cancer and biochemical recurrence. Future work will evaluate the cumulative and interactive effects of the associations within this pathway on prostate cancer risk and recurrence. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2832.