The Clinical Use Of P2PSA And Gene Diagnosis For Predicting Prostate Cancer And High Grade Prostate Cancer

With an estimated914,000new cases and258,000deaths every year globally, prostate cancer (PCa) has become one of the most common malignant tumors in the western countries. China, as an East Asian country, the relatively low incidence and mortality rates are reported, however, they are increasing rapidly, especially in developed metropolitan areas (for instance, in Shanghai, the incidence of PCa rose from1.6/100,000person-years in1972to7.7/100,000person-years in2000). This might be caused by multi-factors, such as change of diet preferences, environmental pollution, etc. As early detection is the key for curative treatment for PCa, a number of early detection biomarkers and diagnostic tools (such as image techniques, PCa risk calculators, etc.) were introduced in the past decades.In the late1980s, Prostate-specific antigen (PSA) was introduced, and was proofed having significant association with PCa. However, with the increasing use of PSA test, limitations have been found because of its low specificity, which might cause a number of over-diagnoses and over-treatments. This might bring the burden for the patients and the economic of society. Thus, it is essential to find more accurate tools for predicting the outcomes of prostate biopsy. In recent years, a variety of prostate-specific biomarkers have been introduced and used. Meanwhile, with the soar of Human Genome Project, numbers of PCa risk-associated genes have been found which may become a revolutionary tool for predicting PCa.Our objectives in this study are as following:(1) To summarize the outcomes and trends of prostate biopsy for prostate cancer based on Chinese population from2003to2011;(2) To investigate the ability of a new biomarker---p2PSA for predicting PCa based on Chinese population;(3) To find the possible PCa risk-associated genes (single nucleotide polymorphisms) in Chinese population;(4) To build a prediction tool based on the risk-associated SNPs. Part ⅠThe Association Between Prostate-Specific Antigen (PSA) and Prostate Biopsy in Chinese Population:Outcomes and Trends of Prostate Biopsy for Prostate Cancer in Chinese Men from2003to2011Background:Prostate-specific antigen (PSA) screening is growing in popularity in China, but its impact on biopsy characteristics and outcomes are poorly understood. Our objective was to characterize prostate biopsy outcomes and trends in Chinese men over a10-year period, since the increasing use of PS A tests.Methods:All men (n=1,650) who underwent prostate biopsy for PCa at Huashan Hospital, Shanghai, China from2003-2011were evaluated. Demographic and clinical information was collected for each patient, including age, digital rectal examination (DRE), transrectal ultrasound (prostate volume and nodule), total prostate-specific antigen (tPSA) levels and free PSA ratio (fPSA/tPSA) prior to biopsy. Prostate biopsy was performed using six cores before October2007or ten cores thereafter. Logistic regression and multivariate analysis were used to evaluate our data.Results:The overall positive rate of prostate biopsy for PCa was47%and the rate decreased significantly over the years from74%in2003to33%in2011(P-trend=0.004). Age at diagnosis was slightly increased (P-trend=0.04) while fPSA/tPSA was significantly decreased (P-trend=1.11X10-5). A statistically significant trend was not observed for tPSA levels, prostate volume, or proportion of positive nodule. The model including multiple demographic and clinical variables (i.e., age, DRE, tPSA, fPSA/tPSA and transrectal ultrasound results)(AUC=0.93) statistically outperformed models that included only PSA (AUC=0.85) or fPSA/tPSA (AUC=0.66) to predict PCa risks (P<0.05). Similar results were observed in a subgroup of men whose tPSA levels were lower than20ng/mL (AUC=0.87, vs. AUC of tPSA=0.62, P<0.05).Conclusions:Detection rates of PCa and high-grade PCa among men that underwent prostate biopsy at the institution has decreased significantly in the past10years, likely due to increasing use of PSA tests. Predictive performance of demographic and clinical variables of PCa was excellent. These variables should be used in clinics to determine the need for prostate biopsy. Part IIThe Ability of Prostate-Specific Antigen (PSA) Isoform p2PSA for Predicting Prostate Cancer in Chinese Population:p2PSA is a Better Biomarker for Predicting Prostate Cancer and High Grade Prostate Cancer than Total PSA and Ratio of Free PSA to Total PSA (%fPSA)Background:Prostate specific antigen (PSA) and its derivatives such as ration of free PSA (fPSA) to total PSA (%fPSA), PSA density (PSAD) has poor specificity for prostate cancer (PCa) and high grade PCa (Gleason Socre>7) prediction. A precursor form of PSA named p2PSA has been found recently, and has been proofed to have significant relationship with PCa prediction in Caucasian population. Our objective is to investigate the detection ability of p2PSA and its derivatives for PCa and high grade PCa in Chinese population.Methods:This was an observational prospective study with the study population consisted of men with tPSA level over4.0ng/mL who were recommended to receive initial prostate biopsies (10cores systematic needle biopsy) in our institute from December2011to November2012. Blood samples were collected on the day of prostate biopsy. tPSA,%fPSA, PSAD, p2PSA,%p2PSA(=[p2PSA/fPSA]×100), Beckman Coulter Prostate Health Index(Phi=p2PSA/fPSA×VtPSA) and Phi density (=phi/prostate volume) were measured. Areas (AUC) under the receiver operating curves (ROC) were evaluated to compare the abilities of these tests for PCa and high grade PCa prediction.Results:A total of221men were finally included in this study.94(42.5%) out of221men were diagnosed as PCa, and66(29.9%) men were diagnosed as high grade PCa. In the entire study population,%p2PSA (AUC=0.86), phi (AUC=0.87) and phi density (AUC=0.90) outperformed tPSA (AUC=0.76, all P<0.01and%fPSA (AUC=0.70, all P<0.01) for predicting PCa. However, when predicting high grade PCa,%p2PSA (AUC=0.84), Phi (AUC=0.88) and Phi density (AUC=0.88) did not show a significant better prediction ability than tPSA (AUC=0.82, P>0.05). In stratified population with tPSA level from4ng/mL to50ng/mL, besides the same results observed in the entire population, Phi density (AUC=0.83) was found having better performance for predicting high grade PCa than tPSA(AUC=0.71, P=0.03).Conclusion:To the best of our knowledge, this is the first study to investigate the prediction ability of p2PSA and its derivatives for PCa and high grade PCa based on Chinese population.%p2PSA, Phi and Phi density have better ability for predicating PCa and high grade PCa than tPSA and%fPSA in Chinese population. This result might be used in decision making of prostate biopsy. Part ⅢA Genetic Study for Prostate Cancer in Chinese Population:Evaluation of Reported Prostate Cancer Risk-Associated SNPs from Genome-wide Association Studies of Various Racial Populations in Chinese MenBackground:Several genome-wide association studies (GWAS) of prostate cancer (PCa) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with PCa risk in various racial groups. The objective of this study is to evaluate which of these SNPs are associated with PCa risk in Chinese men and estimate their strength of association.Methods:All SNPs that were reported to be associated with PCa risk in GWAS from populations of European, African American, Japanese, and Chinese descent were evaluated in1,922PCa cases and2,175controls selected from the Chinese Consortium for Prostate Cancer Genetics (ChinaPCa). A logistic regression analysis was used to estimate allelic odds ratios (ORs) of these SNPs for PCa.Results:Among the53SNPs,50were polymorphic in the Chinese population. Of which,10and24SNPs were significantly associated with PCa risk in Chinese men at P<0.001and <0.05, respectively. These24significant SNPs included17,5, and2SNPs that were originally discovered in European, Japanese, and Chinese descent, respectively. The estimated ORs ranged from1.10to1.49and the direction of association was consistent with previous studies. When ORs were estimated separately for PCa with Gleason score<7and>8, a marginally significant difference in ORs was found only for two of the24SNPs (P=0.02and0.04).Conclusion:About half of PCa risk-associated SNPs identified in GWAS of various populations are associated with PCa risk in Chinese men. Information on PCa risk-associated SNPs and their ORs may facilitate risk assessment of PCa risk in Chinese men Part ⅣPrediction of Prostate Cancer by Risk-associated SNPs:Prediction of Prostate Cancer from Prostate Biopsy in Chinese Men Using a Genetic Score Derived from24Prostate Cancer Risk-associated SNPsBackground:Twenty-four prostate cancer (PCa) risk-associated single nucleotide polymorphisms (SNPs) in Chinese men have been cataloged. We evaluated whether these SNPs can independently predict outcomes of prostate biopsy, and improve the predictive performance of existing clinical variables.Methods:Three-hundreds and eight consecutive patients that underwent prostate biopsy for detection of PCa at Huashan Hospital, Shanghai, China between April2011and August2012were recruited. Clinical variables such as serum prostate-specific antigen (PSA) levels and peripheral blood samples were collected prior to a10-core biopsy. A genetic score based on these24PCa associated SNPs was calculated for each individual.Results:Among308patients underwent prostate biopsy,141(45.8%) were diagnosed with PCa. Genetic score was significantly higher in patients with PCa (median=1.30) than without (median=0.89),P=3.81×10-6. The difference remained significant after adjusting for age and total PSA, P=0.007. The PCa detection rate increased with increasing genetic score;26.3%,43.2%, and60.0%for men with lower (<0.5), average (0.5-1.5), and higher (>1.5) genetic score, respectively, P.trend=0.0003. For patients with moderately elevated PSA levels (1.6-20ng/mL), the PCa detection rate was31.2%overall and was16.7%,31.2%, and40.9%for men with lower (<0.5), average (0.5-1.5), and higher (>1.5) genetic score, respectively, P-trend=0.03. For patients with PSA>=20ng/mL, however, the PCa detection rates were high (>69%) regardless of genetic score.Conclusion:A genetic score based on PCa risk-associated SNPs is an independent predictor of prostate biopsy outcomes in Chinese men and may be helpful to determine the need for prostate biopsy among patients within a "gray zone" of PCa risk.