Variants in the prostate-specific antigen (PSA) gene and prostate cancer risk, survival, and circulating PSA

Severi G, Hayes VM, Neufing P, Padilla EJ, Tilley WD, Eggleton SA, Morris HA, English DR, Southey MC, Hopper JL, Sutherland RL, Boyle P, Giles GG (2006) Variants in the prostate-specific antigen (PSA) gene and prostate cancer risk, survival, and circulating PSA. Cancer Epidemiol Biomarkers Prev 15:1142-1147

An A to G substitution, rs925013, in the promoter of the prostate-specific antigen gene (PSA) was recently found to be associated with promoter activity and circulating PSA levels. The objective of this study was to test the associations between rs925013 and another A to G substitution, rs266882, in the PSA gene with prostate cancer risk using a population-based case-control study of 821 prostate cancer cases and 734 controls carried out in Perth and Melbourne, Australia. The study focused on young (i.e., < 70="" years)="" and="" aggressive="" cases="" (i.e.,="" well-differentiated="" tumors="" were="" excluded).="" cases="" in="" the="" melbourne="" arm="" of="" the="" study="" (n="638)" were="" followed="" up="" prospectively="" for="" an="" average="" period="" of="" 8.2="" years="" and="" deaths="" from="" prostate="" cancer="" ascertained="" through="" record="" linkage="" to="" study="" the="" possible="" association="" between="" genetic="" variants="" and="" disease-specific="" survival.="" psa-circulating="" levels="" were="" measured="" in="" controls="" to="" test="" the="" association="" with="" the="" genetic="" variants="" using="" a="" cross-sectional="" design.="" linear="" regression="" of="" log="" psa="" levels,="" unconditional="" logistic="" regression,="" cox="" regression,="" and="" haplotype="" analyses="" were="" undertaken.="" for="" rs925013,="" the="" g="" allele="" was="" associated="" with="" an="" increased="" risk="" of="" prostate="" cancer="" [odds="" ratio,="" 1.4;="" 95%="" confidence="" interval="" (95%="" ci),="" 1.1-1.7;="" p="0.001]," and="" the="" hazard="" ratio="" for="" survival="" for="" cases="" homozygous="" for="" the="" g="" allele="" compared="" with="" cases="" homozygous="" for="" the="" a="" allele="" was="" increased="" but="" not="" statistically="" significant="" (hazard="" ratio,="" 2.3;="" 95%="" ci,="" 1-5.6;="" p="0.06)." for="" rs266882,="" there="" was="" no="" association="" with="" overall="" prostate="" cancer="" risk="" and="" survival="" (all="" p=""> 0.1). Men homozygous or heterozygous for the G/G (rs925013/rs266882) haplotype were at higher risk of prostate cancer than men homozygous for the A/A haplotype (odds ratio, 1.3; 95% CI, 1.1-1.7; P = 0.009). Adjusted geometric means of circulating PSA levels in controls were similar in men with zero, one, and two copies of the G allele in rs266882 (1.2, 1.1, and 1.3 ng/mL, respectively; all P > or = 0.2) and rs925013 (1.1, 1.2, and 1.5 ng/mL, respectively; all P > 0.1). For rs925013, our study provides good evidence of association with prostate cancer risk, marginal evidence of association with survival, and little evidence of detectable association with circulating PSA levels in controls. We found no evidence of an independent association between rs266882 and any of the outcomes. The genotypes and haplotypes studied might be associated with the PSA gene function or be in linkage disequilibrium with other unmeasured and functional variants in the PSA or other genes.