title: Genetic factors in catechol estrogen metabolism in relation to the risk of endometrial cancer.
abstract: 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.
authors.affiliation: Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, P.O. Box 19024 (M4-C308), Seattle, WA 98109-1024, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Doherty
authors.forename: Noel S
authors.initials: NS
authors.lastname: Weiss
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Freeman
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Dightman
authors.forename: Perry J
authors.initials: PJ
authors.lastname: Thornton
authors.forename: John R
authors.initials: JR
authors.lastname: Houck
authors.forename: Lynda F
authors.initials: LF
authors.lastname: Voigt
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Rossing
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Schwartz
authors.forename: Chu
authors.initials: C
authors.lastname: Chen
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D016889:Endometrial Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D002393:Estrogens, Catechol / Q000378:metabolism*; D005260:Female; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D008875:Middle Aged; D011110:Polymorphism, Genetic; D012307:Risk Factors
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D002394:Catechol O-Methyltransferase; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D002393:Estrogens, Catechol; D005982:Glutathione Transferase; C585496:CYP1B1 protein, human; C413545:glutathione S-transferase T1