No association between genetic polymorphisms in insulin and insulin receptor substrate-1 and prostate cancer.

High levels of insulin and insulin-like growth factors have been associated with increased risk of prostate cancer (1, 2). Insulin regulates and stimulates cell growth, and inhibits apoptosis in cellular models, although mitogenicity seems to occur at supraphysiologic levels. Insulin also inhibits transcription of insulin-like growth factor binding protein-1 and decreases the synthesis of sex hormone binding proteins. Therefore, insulin may increase the unbound circulating insulin-like growth factors and the bioavailability of testosterone for hormone-dependent tissues such as the prostate. Insulin receptor substrate 1 (IRS1) is the primary docking molecule for the receptor and is required for activation of the phosphoinositol-3-kinase pathway, which regulates insulin-like growth factor – mediated survival, enhancement of cellular motility, and antiapoptosis; and for activation of the RAS-mitogen-activated protein kinase pathway, which regulates cell proliferation. Thus, genetic variations in insulin (INS ) and IRS1 may affect an individual’s risk of prostate cancer. A single nucleotide polymorphism (+1127 INS-PstI) located in the 3V untranslated region of INS is hypothesized to have a functional effect on the expression of INS. This polymorphism is also in tight linkage disequilibrium with the variable number of tandem repeat polymorphism that is believed to have a direct effect on insulin regulation. The CC genotype has been associated with a 3-fold increased risk of prostate cancer in one recent case-control study (3). Another study reported a statistically significant association of the IRS1 G972R (Gly!Arg) polymorphism and advanced prostate cancer, although there was no association for INS +1127 INS-PstI (4). The role of the INS +1127 INS-PstI and IRS1 G972R polymorphisms in the etiology of prostate cancer thus remains unclear. We present here the results from a sibling-matched case-control study to further clarify the potential relation of these two genetic polymorphisms with prostate cancer. Materials and Methods