Steroidogenic Germline Polymorphism Predictors of Prostate Cancer Progression in the Estradiol Pathway

Abstract

Purpose: Reliable biomarkers that predict prostate cancer outcomes are urgently needed to improve and personalize treatment approaches. With this goal in mind, we individually and collectively appraised common genetic polymorphisms related to estradiol metabolic pathways to find prostate cancer prognostic markers.Methods: The genetic profiles of 526 men with organ-confined prostate cancer were examined to find common genetic polymorphisms related to estradiol metabolic pathways and these findings were replicated in a cohort of 213 men with more advanced disease (follow-up time for both cohorts, >7.4 years). Specifically, we examined 71 single-nucleotide polymorphisms (SNP) in SULT2A1, SULT2B1, CYP1B1, COMT, CYP3A4, CYP3A5, CYP3A43, NQO1, and NQO2 and assessed the impact of the SNPs alone and in combination on prostate cancer progression and on circulating hormone levels.Results: According to a multivariate analysis, CYP1B1 (rs1800440), COMT (rs16982844), and SULT2B1 (rs12460535, rs2665582, rs10426628) were significantly associated with prostate cancer progression and hormone levels. Remarkably, by combining the SNP information with previously identified HSD17B2 markers, the patients could be stratified into four distinct prognostic subgroups. The most prominent association was observed for the eight-marker combination [CYP1B1 (rs1800440), SULT2B1 (rs12460535, rs2665582, and rs10426628), and HSD17B2 (rs4243229, rs1364287, rs2955162, and rs1119933)].Conclusion: This study identified specific germline variations in estradiol metabolism-related pathways, namely CYP1B1, SULT2B1, and HSD17B2, as novel prognostic markers that are cumulatively associated with increased risk of prostate cancer progression. This panel of markers warrants additional investigation and validation to help stratify patients according to their risk of progression.

Overexpression of SULT2B1b Promotes Angiogenesis in Human Gastric Cancer

“…These conflicting results indicate that the role of SULT2B1b in different cancers is varies with the type of cancer. Recently, several single-nucleotide polymorphisms (SNP) in SULT2B1 gene have been reported to be associated with risk of progression in prostate and esophageal carcinomas [28,29]. Additionally, earlier studies demonstrated that expression of SULT2B1b was significantly increased in breast and liver cancer tissues relative to their corresponding non-tumor counterparts [7,30,31].…”

Sex steroids in the tumor microenvironment and prostate cancer progression

“…Finally, the 1245C variant also appears to be a predictor of sensitivity to the steroidal CYP17 inhibitor abiraterone . Genomic variation in estrogen-related genes has also been reported in PCa patients (Lévesque et al 2014). This includes somatic polymorphisms in CYP1B1, HSD17B2, SULT2B1 and COMT genes.…”

“…This includes somatic polymorphisms in CYP1B1, HSD17B2, SULT2B1 and COMT genes. Further, the cumulative number of alterations appears to correlate with poorer outcome (Lévesque et al 2014). Similarly, SNPs in the CYP19A1 aromatase are associated with concomitant changes in serum estrogen levels and poorer PCa survival, but have no effect on PCa incidence (Travis et al 2009, Kanda et al 2015.…”

The UGT1 locus is a determinant of prostate cancer recurrence after prostatectomy

“…Germline variations in genes involved in the biosynthesis and metabolism of androgens and estrogens have been associated with progression of PCa , Levesque et al 2013, 2014a. The relevance of studying steroidogenic pathways in the context of progression of PCa arises from observations that PCa tumor cells can use multiple biotransforming pathways to de novo synthesize more potent hormones (Montgomery et al 2008, Mitsiades et al 2012.…”

“…In support of these results, we have recently reported that singlenucleotide polymorphisms (SNPs) in genes associated with E 2 -related metabolic pathways, either individually or in combination, are predictors of progression of PCa. These variants are located in genes encoding cytochrome P450 1B1, which is involved in the production of 4-hydroxy metabolites of E 2 and E 1 (4-OH), catechol-O-methyltransferase, which forms 2-methoxy catechol estrogens, sulfotransferase 2B1, which catalyzes the formation of less-reactive sulfate metabolites, and 17b-hydroxysteroid dehydrogenase type 2, which is involved in the conversion of E 2 to E 1 (Levesque et al 2014a). However, it remains unclear whether the outcome of PCa is influenced by common germline polymorphisms in the estrogen catabolic pathway mediated by UGT1 gene products.…”