Germline Mutations and Polymorphisms of Androgen Receptor in Prostate Cancer Patients: Frequency and Results of in Silico Analysis

Abstract

Background: Germline and somatic polymorphisms and mutations of the Androgen Receptor (AR) gene are known to<br />be associated with the incidence of prostate cancer (PCa) in different populations. In this study we assessed germline AR<br />polymorphisms and mutations in PCa patients with prediction of pathogenicity of the identified mutations by in silico<br />analysis. Methods: Diagnosis of PCa was based on histopathology of prostate tissue (Gleason Score criteria) and serum<br />prostate-specific antigen (PSA) levels. Genomic DNA was extracted from peripheral blood of 38 patients. All exons and<br />exon-intron boundaries of AR were amplified using polymerase chain reactions (PCR) followed by Sanger sequencing.<br />In silico analysis was performed using Polyphen-2 and Mutation Taster®. Results: Two polymorphisms, CAG repeat<br />sequence (13-34 repeats in length) and p.Pro214Glu (MAF: 0.0789) located in exon 1 were identified. A missense<br />mutation (c.47C>A/p.Pro146Glu) and in-frame deletion of a CAG sequence leading to loss of Arginine at codon 85<br />(c.252_254delCAG/p.Arg85-) were identified in a 70 year old patient with a Gleason Score and PSA level of 2 and<br />2.4ng/dL, respectively. His PSA level decreased to < 0.5 ng/dL after 9 months of androgen deprivation therapy. Identified<br />mutations were predicted to be non-disease causing by Polyphen-2 and Mutation Taster®. Conclusion: Our data<br />demonstrated that the frequency of germline mutations of AR was low in PCa patients in Indonesia (5.26%: 2/38 alleles),<br />so that they are not likely to be major etiological factors. The in silico analysis of identified AR mutations in this study<br />corroborated the clinopathology features of the patient.