Association Of Genetic Variants In Telomere-related Genes With Prostate Cancer Risk And Recurrence

Part 1 Association of Genetic Variants in Telomerase-related Genes with Prostate Cancer Risk and RecurrenceTelomere-related genes play an important role in carcinogenesis and progression of prostate cancer (PCa). It is unknown whether genetic variations in telomere-related genes are associated with development and progression in PCa patients. We evaluated six potentially functional single nucleotide polymorphisms (SNPs) of three key telomere-related genes in 1015 PCa cases and 1052 cancer-free controls and tested associations of these, SNPs with risk of PCa. Among 426 Pca patients who underwent radical prostatectomy (RP), the prognostic significance of the studied SNPs on biochemical recurrence (BCR) was assessed using the Kaplan-Meier analysis and Cox proportional hazards regression model. The relative telomere lengths (RTL) were measured in peripheral blood leukocytes using real-time PCR in RP patients. We found that TEP1 rs1760904 variant was significantly associated with both decreased risk of PCa (odds ratio [OR]:0.75,95% confidence interval [CI]:0.62-0.91, P= 0.003) and longer RTL (OR:1.55,95% CI:1.04-2.30, P=0.031). A significant interaction of TEP1 rs1713418 with age in modifying the risk of PCa was observed (P=0.005). After adjustment for clinicopathologic risk factors, the presence of heterozygotes or rare homozygotes of TEP1 rs1760904 and TNKS2 rs1539042 were associated with BCR after RP in our cohorts (hazard ratio [HR]:0.54,95% CI:0.36-0.81, P=0.003 and HR:1.64,95% CI: 1.09-2.46, P=0.019). Our data suggest that genetic variations in telomere-related genes may be helpful to predict for risk of PCa and biochemical recurrence after RP.Part 2 Association of Genetic Variants in Telomere Maintenance Genes With Prostate Cancer Risk and RecurrencePCa cells that have escaped from telomere checkpoint generally have two defining hallmarks, telomere loss and reactivation of telomerase. In addition to be involved in PCa development, telomeres may also play a role in disease progression, and there are indications that tumor telomere alteration may prove to be a useful prognostic marker of post-prostatectomy BCR. Theoretically, functional genetic variants that affect telomere elongation, activation of telomerase and configuration of telomeric proteins could lead to some accelerated genetic changes responsible for cancer development and further growth advantages. In this study of 1015 PCa cases and 1052 cancer-free male controls, we investigated associations between potentially functional SNPs in telomere-related genes and Pca risk as well as BCR risk in Chinese men. We found that the RTEL1 rs2297441 and rs3208008 rare homozygotes were associated with an increased risk of PCa compared with major homozygotes (OR:1.44,95% CI:1.08-1.93and OR:1.37,95% CI:1.08-1.93). Further in vitro and ex vivo functional experiments demonstrated that the RTEL1 rs2297441 variant A allele strengthened the binding affinity of miR-103 to the RTEL1 3’-untranslated region (UTR) in three cancer cell lines, resulting in change of the RTEL1 expression. In the RP subset, the RTEL1 rs2297441 and rs3208008 were significantly associated with both biochemical recurrence after RP and longer RTL. Taken together, the RTEL1 rs2297441 SNP may function by affecting the affinity of miR-103 binding to the 3’-UTR of RTEL1 and regulating RTEL1 expression, thus contributing to prostate cancer risk. Additionally, RTEL1 rs2297441 and rs3208008 may predict risk of PCa and biochemical recurrence in RP patients.Part 3 Genetic Variations of the ADIPOQ Gene And Prostate Cancer Risk in Chinese Han MenAdiponectin secreted by adipose tissue has been implicated in prostate carcinogenesis. Genetic variations in ADIPOQ are thought to influence the activity of adiponectin, thus relating to cancer occurrence. In this hospital-based case-control study of 917 PCa cases and 1,036 cancer-free controls, we evaluated the association of SNPs in ADIPOQ gene with risk of PCa and adiponectin levels in Chinese Han men. Variants of ADIPOQ gene were genotyped by Taqman polymerase chain reaction method. The plasma adiponectin concentrations were measured by enzyme-linked immunosorbent assay (ELISA) in a subset of cases and controls. We found that ADIPOQ rs3774262 variant AA genotype was associated with both decreased PCa risk (adjusted OR:0.66,95% CI=0.48-0.92 and increased plasma adiponectin levels (p=0.036 and 0.043), with significant difference by tumor grade, clinical stage and aggressiveness. A significant interaction between ADIPOQ rs3774262 and body mass index (BMI) was observed in modifying the risk of Pca (P= 6.7×10-3). ADIPOQ rs266729 and rs182052 were not related to PCa risk or plasma adiponectin levels. Our data support ADIPOQ rs3774262 may affect PCa risk in combination with plasma adiponectin levels in Chinese Han men. It may contribute to the molecular basis for the association between obesity and PCa.