Genetic polymorphisms in oestrogen receptor-binding sites affect clinical outcomes in patients with prostate cancer receiving androgen-deprivation therapy
Journal
Journal of Internal Medicine
Journal Volume
271
Journal Issue
5
Pages
499-509
Date Issued
2012
Author(s)
Huang C.-N.
Huang S.-P.
Pao J.-B.
Hour T.-C.
Chang T.-Y.
Lan Y.-H.
Lu T.-L.
Lee H.-Z.
Juang S.-H.
Wu P.-P.
Hsieh C.-J.
Bao B.-Y.
Abstract
Background. Accumulating evidence indicates that oestrogens have significant direct effects on normal prostate development and carcinogenesis. The majority of the biological activities of oestrogens are mediated through the oestrogen receptor (ER), which functions as a hormone-inducible transcription factor to regulate target gene expression by binding to oestrogen response elements (EREs) in the regulatory regions of target genes. Sequence variants in EREs might affect the ER-ERE interaction and subsequent physiological activities. Therefore, we tested whether common single-nucleotide polymorphisms (SNPs) inside EREs are related to the clinical outcomes of androgen-deprivation therapy (ADT) in men with prostate cancer. Methods. We systematically evaluated 49 ERE SNPs predicted using a genome-wide database in a cohort of 601 men with advanced prostate cancer treated with ADT. The prognostic significance of these SNPs on disease progression, prostate cancer-specific mortality (PCSM) and all-cause mortality (ACM) after ADT was assessed using Kaplan-Meier analysis and a Cox regression model. Results. Based on multiple hypothesis testing, BNC2 rs16934641 was found to be associated with disease progression; in addition, TACC2 rs3763763 was associated with PCSM, and ALPK1 rs2051778 and TACC2 rs3763763 were associated with ACM. These SNPs remained significant in multivariate analyses that included known clinicopathological predictors. Moreover, a combined genotype effect on ACM was observed when ALPK1 rs2051778 and TACC2 rs3763763 were analysed in combination. Patients with a greater number of unfavourable genotypes had a shorter time to ACM during ADT (P for trend <0.001). Conclusion. The incorporation of ERE SNPs into models with known predictors might improve outcome prediction in patients with prostate cancer receiving ADT. ? 2011 The Association for the Publication of the Journal of Internal Medicine.
Subjects
Androgen-deprivation therapy; Oestrogen receptor; Oestrogen response element; Prostate cancer; Single-nucleotide polymorphism
SDGs
Other Subjects
antiandrogen; estrogen receptor; gonadorelin agonist; adult; aged; androgen deprivation therapy; article; binding site; estrogen responsive element; genetic polymorphism; genotype; human; major clinical study; male; nucleotide sequence; priority journal; prostate cancer; single nucleotide polymorphism; treatment outcome; Aged; Androgen Antagonists; Androgens; Antineoplastic Agents, Hormonal; Databases, Genetic; Disease Progression; Estrogens; Gene Expression Regulation; Genome-Wide Association Study; Humans; Kaplan-Meier Estimate; Male; Polymorphism, Single Nucleotide; Proportional Hazards Models; Prostate; Prostatic Neoplasms; Receptors, Estrogen; Transcription Factors; Tumor Suppressor Proteins
Type
journal article