The polymorphism GSTP1 codon 105 might be associated with biochemical recurrence in Argentine localized prostate cancer patients treated with radical prostatectomy.

COTIGNOLA J; SHAHABI A; LEONARDI D; STERN M; NAVONE N; SCORTICATI C; DE SIERVI A; MAZZA O; VAZQUEZ E

Orlando

Congreso; AACR - Advances in Prostate Cancer Research; 2012

  Background: Prostate Cancer (PCa) is the second type of cancer diagnosed in men and the sixth cause of cancer-related deaths worldwide. The GLOBOCAN 2008 project estimated that, in Argentina, the PCa incidence and mortality rates were 58.8 and 15.6 per 100,000 men, respectively; making it the second cause of cancer-related deaths among Argentine men. Prostate-Specific Antigen (PSA) is being used as a biomarker for early detection of PCa However, the ability to determine whether a primary tumor is able to recur or metastasize has not been accomplished yet, because none of the biomarkers currently used have shown sufficient predictive value or sensitivity to foresee PCa progression. Aim: the goal of the study was to identify new genetic markers that can be used as additional tools to better predict PCa progression. Methods: we have retrospectively recruited 122 patients diagnosed with PCa from one Hospital Center in Buenos Aires, Argentina. All patients underwent radical prostatectomy (RP) as therapeutic strategy. The study protocol was approved by the Ethic Committee and follows the ethical principles enunciated by the Declaration of Helsinki. All patients signed an informed consent before blood donation for DNA analyses. We genotyped five polymorphisms in enzymes involved in: i) drug metabolism (GSTPi p.105 Ile>Val, GSTT1 null and GSTM1 null), ii) xenobiotic efflux (MDR1 c.3435C>T, rs1045642), and iii) DNA synthesis (MTHFR c.677C>T,rs1801133). The GSTPi, MDR1 and MTHFR polymorphisms were genotyped by PCR-RFLP;the other two (GSTT1 and GSTM1), were genotyped by multiplex-PCR. We performed univariate and multivariate Cox regression models to study the association between these polymorphisms and PCa biochemical recurrences after RP. Biochemical recurrence was defined as an increase in serum PSA after RP. We calculated the Hazard Ratios (HR) and 95% confidence intervals (95%CI).Survival analyses were performed by Kaplan-Meier curves and the comparison between genotypes was done using the log-rank test. Results: The univariate analysis of GSTPi p.105 Ile>Val showed an increased risk of biochemical recurrence for homozygote Val patients compared to homozygote Ile patients (HR=3.19; 95%CI= 1.27-8.03; p=0.014). This association remained significant after adjustment for Gleason score and PSA at diagnosis (HR=2.49; 95%CI=1.03-6.00; p=0.037). Heterozygote patients showed a small increased risk; however, it was not significant (HR=1.14; 95%CI=0.53-2.46). The analysis of Recurrence-Free Survival (RFS) revealed that homozygote Val patients hadpoorer RFS compared to the other genotypes in univariate analysis (log-rank p=0.023) and after adjustment for cofounders (p=). Nostatistical significant associations between MDR1, MTHFR, GSTT1 and GSTM1 polymorphisms and biochemical recurrence were found. We excluded 16 patients (13%) from the final analyses that showed elevated PSA after RP (persistent disease). Discussion: Our results associates for the first time the polymorphism GSTPi p.105 Ile/Val  with the risk of developing a biochemical recurrence after RP in multivariate analyses in the Argentinean population. The use of this tool in PCa patients might facilitate the prediction of PCa recurrenceinfluencing the selection of  the best therapy schema for each patient.