Genetic factors in catechol estrogen metabolism in relation to the risk of endometrial cancer.

2-Hydroxylated metabolites of estrogen have been shown to have antiangiogenic effects and inhibit tumor cell proliferation, whereas 4-hydroxylated metabolites have been implicated in carcinogenesis. We examined whether polymorphisms in certain genes involved in estrogen metabolism are associated with endometrial cancer risk in a population-based case-control study with 371 cases and 420 controls. Based on previously published genotype-phenotype correlation studies, we defined variant alleles thought to increase estrogen 2-hydroxylation as presumptively low-risk (CYP1A1 m1 T6235C and m2 Ile(462)Val) and those thought to increase estrogen 4-hydroxylation as high-risk (CYP1A1 m4 Thr(461)Asn, CYP1A2 A734C, and CYP1B1 Leu(432)Val). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression. Carrying at least one CYP1A1 m1 or m2 variant allele was associated with a decreased risk of endometrial cancer [ORs (95% CIs), 0.64 (0.44-0.93) and 0.54 (0.30-0.99), respectively]. No strong alteration in risk was observed among women with any of the putative high-risk alleles. When CYP1A1, CYP1A2, and CYP1B1 genotypes were combined and ranked by the number of putative low-risk genotypes carried, women with four or five low-risk genotypes had a reduced risk of endometrial cancer (OR, 0.29; 95% CI, 0.15-0.56) compared with women with one or none. No appreciable alteration in risk was observed among women carrying two or three low-risk genotypes. Some of our findings are consistent with the hypothesis that increased estrogen 2-hydroxylation is associated with decreased endometrial cancer risk, but replication of these results is required before any firm conclusions can be reached.

Androgen receptor polymorphisms and the incidence of prostate cancer.

The human androgen receptor gene contains polymorphic CAG and GGC repeats in exon 1. We investigated whether the number of CAG and/or GGC repeats is related to prostate cancer risk in a case-control study nested within the beta Carotene and Retinol Efficacy Trial. Among 300 cases and 300 controls, we did not observe any increase in risk associated with fewer CAG or GGC repeats. We observed a nonsignificant decrease in risk associated with each unit of decrease in CAG length [odds ratio (OR), 0.98; 95% confidence interval (CI), 0.93-1.03). Men with CAG <22 had a relative risk of prostate cancer of 0.89 (95% CI, 0.65-1.23) compared with men with CAG > or =22. There was no appreciable difference in the mean number of GGC repeats between cases and controls; the estimated change in the risk of prostate cancer associated with one fewer GGC repeat was 0.97 (95% CI, 0.88-1.06). The risk in men at or below the mean number of GGC repeats (17) was 0.80 (95% CI, 0.57-1.12). In contrast to prior reports, men with both short CAG (<22) and short GGC (< or =17) repeats were not at increased risk of prostate cancer (OR, 0.56; 95% CI, 0.32-0.98), compared with men with > or =22 CAG repeats and >17 GGC repeats. Our results do not support the hypothesis that a small number of CAG or GGC repeats in the androgen receptor gene increases a man's risk of prostate cancer.

Polymorphic markers in the 5alpha-reductase type II gene and the incidence of prostate cancer.

In the prostate, the enzyme encoded by the SRD5A2 gene (5alpha-reductase) converts testosterone to dihydrotestosterone, a potent androgen that has been hypothesized to play a role in the genesis of prostate cancer. Several polymorphisms have been identified in the SRD5A2 gene, including a valine-to-leucine substitution (V89L) at codon 89, a variable number of TA dinucleotide repeats and a missense substitution at codon 49 resulting in an amino acid substitution of alanine with threonine (A49T). To investigate the influence of these polymorphisms on prostate cancer risk, we conducted a case-control study nested within the Beta-Carotene and Retinol Efficacy Trial. Genotypes were determined by PCR-based capillary electrophoresis using genomic DNA isolated from 300 cases and 300 controls matched on the basis of race, age at enrollment (within 5 years), enrollment study center and year of randomization. There was no association between V89L genotypes and prostate cancer risk. The age- and race-adjusted odds ratio (OR) associated with the VL and LL genotypes were 1.06 (95% confidence interval (CI) = 0.75-1.49) and 0.99 (95% CI = 0.57-1.73), respectively, as compared to the VV genotype. The age- and race-adjusted odds ratio for men having 1 TA(9) or TA(18) allele was 0.98 (95% CI = 0.64-1.48) when compared to men without TA repeats. The corresponding odds ratio for men without the TA(0) alleles was 0.68 (95% CI = 0.21-2.19). The age- and race-adjusted odds ratio associated with having at least 1 T allele at codon 49 was 1.11 (95% CI = 0.58-2.11), as compared to the AA genotype. Our results do not support the hypothesis that the V89L and A49T polymorphisms in the SRD5A2 gene are related to the risk of prostate cancer, but are compatible with the suggestion from earlier studies that men who are homozygous for the TA(9) or (18) alleles and men who have the TA(9)/TA(18) genotype are at a modestly reduced risk.