Prostate cancer outcomes and polymorphism in LHRH and LH receptors and SHBG.

Abstract

5 Background: The hypothalamic-pituitary-gonadal axis is integral to androgen synthesis and the management of prostate cancer (PC). Genetic variation in the receptors of this pathway may impact the efficiency of signal transduction and overall clinical course. We examined polymorphisms in four receptors central to this pathway: luteinizing hormone-releasing hormone receptor (LHRHR), luteinizing hormone receptor (LHR), androgen receptor (AR) and steroid hormone binding globulin (SHBG). We examined the association between these genotypes and survival. Methods: Patients diagnosed with PC between 1999 and 2004 in Los Angeles County were identified using the Los Angeles County Cancer Registry as part of the California Collaborative Prostate Cancer study, a multiethnic, population based case-control study. Included in this analysis were 1232 men with PC: 631 with advanced stage PC at diagnosis and 430 with high-grade PC. The ethnic breakdown was 376 African-American, 355 Hispanic and 501 Caucasian. DNA was extracted from blood and genotypes for LHR, LHRHR, AR and SHBG were assayed using TaqMan or GeneScan methods. Vital status and cause of death was obtained by linking to the Cancer Registry records. Hazard ratios were estimated by fitting Cox proportional hazards models. Results: As of September 2010, 396 (32%) had died and 122 (10%) had died of PC. In the multivariate model, there was a significant association between disease specific survival and genetic variation in LHRHR, LHR and SHBG. Hazard ratios (HR) for carriers (vs. non-carriers) of the LHR312 minor allele were 1.63 (95% CI: 1.08-2.45) among all cases and 2.04 (1.23-3.39) for high- grade cases. The LHRHR16 minor allele was rare among African Americans; the HR among Caucasians was 1.90 (1.15-3.13) and did not vary by disease grade. The SHGB356 minor allele was associated with survival only among high-grade cases with a HR of 2.38 (1.18-4.81). In addition, when comparing cases to controls, the LHR312 minor allele was inversely associated with PC incidence. Conclusions: Genetic variation in the LHRHR, LHR and SHGB genes are associated with PC survival and warrant further analysis to define their role as prognostic and predictive markers. No significant financial relationships to disclose.