title: Androgen receptor mutations and polymorphisms in African American prostate cancer.
abstract: The Androgen receptor (AR) plays a central role in the normal development of the prostate gland, in prostate carcinogenesis, and in the progression of prostate cancer (PCa) to advanced metastatic disease. African American (AA) men with PCa present with higher tumor volume, more advanced tumor stage, and higher Gleason score. This could be in part related to the AR expression or activity in the prostate tissue of AA men, or to unique mutations or polymorphisms of the AR. In Caucasian Americans (CAs), AR mutations are rare or infrequent in organ-confined tumors, but occur at a higher rate in advanced, metastatic, or castrate-recurrent disease. In AAs, the prevalence, clinical, and biological significance of AR mutations in PCa are unknown. In this study, we investigated the occurrence of somatic and germline AR mutations in patients with primary PCa in AAs compared with CAs. Due to very limited data available on allelic distribution of E213 (G/A) single nucleotide polymorphism (SNP), we also assessed this in patients with sporadic PCa and in unrelated healthy individuals from both ethnic populations. Somatic missense AR mutations were detected at a higher rate in AAs (17 out of 200 cases) than in CAs (2 out of 100 cases). In AAs, the majority of these mutations (41.1%) were from Gleason 7 tumors, a small portion (23.5%) from Gleason 8 tumors, and the rest (35.2%) from Gleason 6 tumors. Analysis of genomic DNAs extracted from white blood cells of patients with sporadic PCa revealed that the rate of germline AR mutations were also higher (~4 times) in AAs than in CAs. With respect to E213 (G/A) SNP, the E213 A-allele expression was 5.85 times higher in healthy unrelated AA men than in CA men. However, in AAs with somatic AR mutation, the E213 G-allele distribution was almost equal to the A-allele. Silencing of one of the somatic AR mutations (i.e., 597 Ser>Gly) in a primary AA-PCa cell line (e.g., E006AA) revealed that similar AR mutation can be associated simultaneously with both "gain-of-function" phenotype (cell migration and invasion) and a "loss-of-function" phenotype (proliferation). Our data demonstrated a higher susceptibility for genetic alterations in the AR in the form of somatic mutations in sporadic PCa or in the form of germline mutations in AAs as compared with CAs. These data may support the idea that AR-specific hypermutator phenotype in combination with other genes, might serve as a contributing factor to ethnic differences in PCa and potentially different clinical outcome in AAs as a high-risk population.
authors.affiliation: 1. Department of Cancer Genetics, Center for Pharmacology and Genetics, Elm and Carlton Streets, Roswell Park Cancer Institute, Buffalo, New York. ; 2. Department of Urology, Center for Pharmacology and Genetics, Elm and Carlton streets, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Shahriar
authors.initials: S
authors.lastname: Koochekpour
authors.affiliation: 3. Department of Biology, Dillard University, New Orleans, Louisiana. ; 4. Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Erick
authors.initials: E
authors.lastname: Buckles
authors.affiliation: 1. Department of Cancer Genetics, Center for Pharmacology and Genetics, Elm and Carlton Streets, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Shourideh
authors.affiliation: 4. Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: SiYi
authors.initials: S
authors.lastname: Hu
authors.affiliation: 5. Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Dhyan
authors.initials: D
authors.lastname: Chandra
authors.affiliation: 4. Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana. ; 6. Department of Pediatrics, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
authors.forename: Jovanny
authors.initials: J
authors.lastname: Zabaleta
authors.affiliation: 7. Department of Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, New York.
authors.forename: Kristopher
authors.initials: K
authors.lastname: Attwood
mesh_terms: D001741:Black or African American / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D011110:Polymorphism, Genetic / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen
keywords: African American; Androgen receptor; mutations; prostate cancer