Sex Hormones, Genetic Polymorphism and Prostate Cancer
Prostate cancer is the most common male malignancy and the second most common cause of cancer-related deaths in United States. The disease is marked by varying rates of progression, response to therapy and age of onset. Recent evidence suggests a possible inherited genetic predisposition to the disease. However, some studies have generated conflicting results due to the relatively small number of participants, or due to the measurement of hormone levels after the diagnosis of prostate cancer. We are conducting a case-control study nested within the Caroten and Retinol Efficacy Trial (CARET) involving 600 participants with 300 prostate cancer patients and 300 controls matched for age, race, time of blood draw, study center and intervention arm. Using serum samples we will determine levels of androgen, estradiol, sex hormone binding globulin and prostate specific antigen. Using genomic DNA extracted from blood spots and serum samples, we will determine genetic polymorphisms of 17-hydroxylase cytochrome P450 and the 5-alpha reductase type-II which converts testosterone into a more potent androgen. We will also analyze genetic polymorphisms of the androgen receptor through which androgens exert their effects. Furthermore, we will investigate the functional significance of these polymorphisms especially the GGN and CAG repeats of androgen receptor, as well as the signal transduction involved down-stream these mutations. Our proposed study have the statistical power to determine the interaction between hormone levels and genetic polymorphisms and the susceptibility of prostate cancer. It will also help elucidate the impact of the mutated androgen receptor on signal transduction pathways.