Association between polymorphisms in sex hormones synthesis and metabolism and prostate cancer aggressiveness

<div><p>Novel biomarkers for prostate cancer (PCa) diagnosis and prognosis are necessary to improve the accuracy of current ones employed in clinic. We performed a retrospective study between the association of several polymorphisms in the main genes involved in the synthesis and metabolism of sex hormones and PCa risk and aggressiveness. A total of 311 Caucasian men (155 controls and 156 patients) were genotyped for 9 SNPs in <i>AR</i>, <i>CYP17A1</i>, <i>LHCGR</i>, <i>ESR1</i> and <i>ESR2</i> genes. Diagnostic PSA serum levels, Gleason score, tumor stage, D´Amico risk and data of clinical progression were obtained for patients at the moment of the diagnosis and after 54 months of follow-up. Chi-squared test were used for comparisons between clinical variables groups, logistic regression for clinical variables associations between SNPs; and Kaplan–Meier for the association between SNPs and time to biochemical progression. We found 5 variants (<i>CYP17A</i>1) rs743572, rs6162, rs6163; (<i>LHCGR</i>) rs2293275 and (<i>ESR2</i>) rs1256049 that were statistically significant according to clinical variables (PSA, D´Amico risk and T stage) on a case-case analysis. Moreover, the presence of </p><p><i>A</i></p> and <p><i>G</i></p> alleles in rs743572 and rs6162 respectively, increase the risk of higher PSA levels (>10 ng/μl). With respect to D´Amico risk rs743572 (<p><i>AG-GG</i></p>), rs6162 (<p><i>AG-AA</i></p>) and rs6163 (<p><i>AC-AA</i></p>) were associated with an increased risk; and last, <p><i>AC</i></p> and <p><i>AA</i></p> genotypes for rs6163 were associated with a shorter biochemical recurrence free survival (BRFS) in patients with radical prostatectomy. In multigene analysis, several variants in SNPs rs2293275, rs6152, rs1062577, rs6162, rs6163, rs1256049 and rs1004467 were described to be associated with a more aggressiveness in patients. However, none of the selected SNPs show significant values between patients and controls. In conclusion, this study identified inherited variants in genes <i>CYP17A1</i>, <i>LHCGR</i> and <i>ESR2</i> related to more aggressiveness and/or a poor progression of the disease. According to this study, new promise PCa biomarkers for clinical management could be included in these previous SNPs.<p></p></div

Summary of clinical variables.

<p>Summary of clinical variables.</p

BRFS according rs6163 (<i>CYP17A1</i>) genotype.

<p>Kaplan-Meier curves of time to biochemical recurrence in patients treated with radical prostatectomy and stratified by rs6163 genotype (<i>CC vs</i>. </p><p><i>AC+AA</i></p>). P value obtained from log-rank t test.<p></p

Significant associations between clinical variables and SNPs in PCa patients.

<p>Significant associations between clinical variables and SNPs in PCa patients.</p

Multivariate analysis for differentially distributed SNPs and clinical variables.

<p>Multivariate analysis for differentially distributed SNPs and clinical variables.</p

Genotyping and Allelic Proportion of SNPs.

<p>Genotyping and Allelic Proportion of SNPs.</p