Genetic alterations of Cyclin D-CDK4/6-INK4-RB pathway in prostate cancer.

BACKGROUND

Alterations in key cell cycle regulators are strongly linked to tumorigenesis. Therefore, we hypothesized that polymorphisms of genes encoded cyclin-dependent kinase 4 and 6 (CDK4 and CDK6), cyclin D1 (CCND1), CDK inhibitors p16 and p15, as well as the retinoblastoma protein (RB), could modulate prostate cancer risk and influence the corresponding mRNA levels.

METHODS AND RESULTS

We evaluated CDK4 rs2069502, CDK6 rs2285332, CCND1 rs9344, p16 rs11515, p15 rs3217986, and RB rs3092904 polymorphisms using TaqMan SNP Assays in a cohort comprising 532 prostate cancer patients and 567 control subjects. Additionally, we measured the relative mRNA expression levels of genes encoding these proteins in RNA derived from 44 prostate tumor tissues and 31 benign prostatic hyperplasia (BPH) tissues using quantitative real-time PCR (qRT-PCR). No statistically significant associations were found between the CDK4 rs2069502, p16 rs11515 and RB rs3092904 polymorphisms and prostate cancer risk. However, the GA genotype of CCND1 rs9344 polymorphism was significantly associated with an increased risk of prostate cancer (OR, 1.64; 95% CI, 1.23-2.20; p < 0.001). Moreover, the relative mRNA expression levels of CCND1, p15 and RB were significantly lower (p<0.05) in prostate tumor tissues compared to BPH tissues. Furthermore, lower relative expression levels of CDK4 and p16 mRNA were associated with elevated serum PSA levels (≥10 ng/ml; p<0.05), while reduced relative expression of p15 was correlated with a higher pathological T stage (pT3/pT4; p<0.05).

CONCLUSIONS

Our findings indicate that genetic alterations, including polymorphisms and/or gene expression changes in the cyclin D1-CDK4-p16/p15-RB pathway, are associated with prostate cancer risk.