PURPOSE: Hormonal manipulation is the mainstay treatment of prostate cancer, notably in advanced stages. Despite initial favorably response, the cancer eventually develops hormone resistance resulting in disease progression and death. However, little is known about genetic determinants of disease progression and prostate cancer-specific death. EXPERIMENTAL DESIGN: We analyzed a population-based cohort comprising 2,761 men diagnosed with prostate cancer from March 2001 to October 2003 and with complete follow-up through July 2006. During a median follow-up time of 3.8 years, a total of 300 men had died from prostate cancer. We genotyped 23 haplotype tagging single nucleotide polymorphisms in the genes AR, CYP17, and SRD5A2 and used Cox proportional hazards analyses to quantify associations between genotype and risk of dying from prostate cancer. RESULTS: The variant 'A' allele of an AR promoter single nucleotide polymorphism, rs17302090, was borderline associated with a 50% increased risk of dying from prostate cancer (95% confidence interval, 1.0-2.3; P = 0.07). This finding was more pronounced in patients who received hormonal therapy as primary treatment at diagnosis (hazard ratio, 1.9; 95% confidence interval, 1.3-2.9; P = 0.007). We did not identify any associations between CYP17 or SRD5A2 variation and prostate cancer-specific death. CONCLUSIONS: Our results suggest that inherited genetic variation in the androgen receptor gene affects hormonal treatment response and ultimately prostate cancer death.
PURPOSE: Hormonal manipulation is the mainstay treatment of prostate cancer, notably in advanced stages. Despite initial favorably response, the cancer eventually develops hormone resistance resulting in disease progression and death. However, little is known about genetic determinants of disease progression and prostate cancer-specific death. EXPERIMENTAL DESIGN: We analyzed a population-based cohort comprising 2,761 men diagnosed with prostate cancer from March 2001 to October 2003 and with complete follow-up through July 2006. During a median follow-up time of 3.8 years, a total of 300 men had died from prostate cancer. We genotyped 23 haplotype tagging single nucleotide polymorphisms in the genes AR, CYP17, and SRD5A2 and used Cox proportional hazards analyses to quantify associations between genotype and risk of dying from prostate cancer. RESULTS: The variant 'A' allele of an AR promoter single nucleotide polymorphism, rs17302090, was borderline associated with a 50% increased risk of dying from prostate cancer (95% confidence interval, 1.0-2.3; P = 0.07). This finding was more pronounced in patients who received hormonal therapy as primary treatment at diagnosis (hazard ratio, 1.9; 95% confidence interval, 1.3-2.9; P = 0.007). We did not identify any associations between CYP17 or SRD5A2 variation and prostate cancer-specific death. CONCLUSIONS: Our results suggest that inherited genetic variation in the androgen receptor gene affects hormonal treatment response and ultimately prostate cancer death.
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Authors: Tristan M Sissung; Douglas K Price; Marzia Del Re; Ariel M Ley; Elisa Giovannetti; William D Figg; Romano Danesi Journal: Biochim Biophys Acta Date: 2014-09-06
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