title: Genetic variants in AR and SHBG and resistance to hormonal castration in prostate cancer.
abstract: Castration resistance is a life-threatening event that may develop in prostate cancer patients with advanced disease following hormonal castration therapy (HCT). Current understanding of the molecular mechanisms behind resistance to hormonal castration suggests a role for androgen receptor signaling and bioavailability of androgens. We evaluated whether common functional polymorphisms in AR and SHBG genes associate with response to HCT. The study included 203 prostate cancer patients with advanced disease treated with hormonal castration. Genomic DNA was isolated from whole blood, and the genetic polymorphisms AR +1733 G>A and SHBG +5790 G>A were determined by real-time PCR. Genetic variants were associated with response to treatment and time to resistance to hormonal castration. Multivariate analysis showed increased risk of developing resistance to hormonal castration in homozygous GG carriers of the SHBG +5790 G>A (HR = 1.9, 95 % CI 1.1-3.3, P = 0.019) polymorphism alone and when functionally combined with AR +1733 G>A into a high AR pathway activation genetic profile (HR = 1.9, 95 % CI 1.1-3.1, P = 0.015), after adjustment for age, PSA, Gleason's score and clinical stage. Our results suggest that the SHBG +5790 G>A polymorphism may be a useful marker to include in the pharmacogenomic profile of prostate cancer resistant to hormonal castration.
authors: Molecular Oncology Group-CI, Portuguese Institute of Oncology, Edificio Laboratorios-Piso 4, Rua Dr António Bernardino Almeida, 4200-072 Porto, Portugal. catiapmonteiro@gmail.com
authors: Cátia
authors: C
authors: Monteiro
authors: Marta Velho
authors: MV
authors: Sousa
authors: Ricardo
authors: R
authors: Ribeiro
authors: Joaquina
authors: J
authors: Maurício
authors: Avelino
authors: A
authors: Fraga
authors: Rui
authors: R
authors: Medeiros
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D000368:Aged; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics*; D011944:Receptors, Androgen / Q000235:genetics*; D012738:Sex Hormone-Binding Globulin / Q000235:genetics*
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen; D012738:Sex Hormone-Binding Globulin
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