Association Of Genetic Polymorphisms Across The TERT Gene,Clinical Parameters And Prostate Cancer Progression

Prostate cancer(PCa) is one of the most common male malignant cancer in Western developed countries. It is a kind of highly heterogeneous disease of which the prognosis of patients may be quite different even with the same pathological and clinical stages. Our study was to evaluate the possible relationships between prostate cancer progression and molecular signatures as well as clinical factors.Part ?. Association of Genetic Polymorphisms across the TERT Gene with Prostate Cancer Aggressiveness in a Chinese Han PopulationObjective: Telomerase reverse transcriptase, expressed by TERT, is essential for the maintenance of telomere DNA length, chromosomal stability and cellular immortality and plays a role in tumorigenesis and cancer progression. The aim of our study was to evaluate the association between common genetic variations across the TERT gene region and PCa aggressiveness in a Chinese population.Methods: 1,210 PCa patients included in our study were grouped as low,intermediate or high risk for clinical recurrence and rapid progression after primary therapy for PCa using D'Amico risk classification criteria and we used a greedy algorithm based on the r2 statistic to find tagging SNPs using Haploview program 4.2 according to the Hap Map database. DNA from these PCa patients were extracted and 12 TERT tagging SNPs were genotyped on the SEQUENOM ?Mass-ARRAY i PLEX? platform.Unconditional logistic regression was used to investigate the association of genotypes with PCa aggressiveness, Gleason grade and risk of developing an early onset PCa.Results: We observed that allele ”C” of the TERT intron2 SNP(rs2736100)was significantly associated with reduced risk of PCa aggressiveness(odds ratio(OR)=0.81, 95% confidence interval(CI): 0.66-0.99, P=0.037).This allele was also significantly correlated with reduced risk of developing a high Gleason grade(>7) tumor(OR=0.83, 95% CI: 0.70-0.99, P=0.039).Allele “T” of intron4 SNP(rs10069690) was found to be significantly associated with a decreased risk for aggressive PCa(OR=0.76, 95%CI:0.59-0.97, P=0.030). In addition, allele “A” of rs10078761 located in the 3'of the TERT gene showed statistically significant association with reduced risk of developing higher grade disease with an OR of 0.48(95% CI:0.28-0.81, P=0.006). However, no association of TERT polymorphisms with age at diagnosis was observed in our study.Conclusions: Our findings demonstrated for the first time that genetic variations across the TERT gene are associated with PCa aggressiveness in a Chinese Han population and the results could help guide the individualized therapy of prostate cancer using molecular signatures in clinical practice.Part ? The relationships between clinical Parameters and the effective time of endocrine therapy for prostate cancer patients in a Chinese Han populationObjective: To evaluate the relationships between the clinical parameters of prostate cancer(PCa) patients and the effective time of endocrine therapy.Methods:The clinical parameters of 432 patients with prostate cancer who accepted endocrine therapy only between 2003 to 2012 at Xinhua Hospital affiliated to Shanghai Jiaotong Univeristy School of Medicine were analyzed in this study. The endpoint of this study was defined as the failure of endocrine therapy which referred to a continuous elevation of prostate specific antigen(PSA) value from nadir twice and greater than0.2ug/L.The clinical parameters including clinical stage,age,initial PSA value,PSA nadir value, Gleason score,bone metastasis,and lymph node metastasis were collected and the relationships between these data and the effective time of endocrine therapy were evaluated using COX regression model.Results: The range of prostate cancer onset age was 57 to 88 years old with a median age of 73.7.The range of initial PSA value was 10.30 to588.10 ng / ml with a median value of 27.15 ng / ml. The range of effective time of endocrine therapy was 3—62 months with a median time of 27.0months.Univariate regression analysis showed that clinical stage,Gleason score,initial PSA,PSA nadir,bone metastasis and lymph node metastasis were correlated with the effective time of endocrine therapy with a P value<0.01.Nevertheless, further multivariate regression analysis showed that only Gleason score was correlated with the effective time of endocrine therapy with a P value of 0.001.Compared with those PCa patients with Gleason Scores?3+4, those with Gleason scores?4+3 had 2.49 fold increased risk of endocrine therapy failure(OR=2.49.95%CI:1.44—4.0).Conclusion : Our study demonstrates that Gleason score is closely correlated with the effective time of endocrine therapy for prostate cancer patients.. For patients with Gleason Score? 4+3 may have poorer response to endocrine therapy than those ?3+4.