Ovarian cancer risk and polymorphisms involved in estrogen catabolism.
Polymorphisms within genes responsible for estrogen catabolism could alter cellular levels of genotoxic 4-hydroxylated catechol estrogens and antiangiogenic 2-methoxyestradiol, thus influencing risk of developing ovarian cancer. We carried out a population-based case-control study of 310 epithelial ovarian cancer cases and 585 controls in African-American and Caucasian women ages 35 to 54 years from Seattle, Atlanta, and Detroit metropolitan areas. Subjects were interviewed and genotyped for CYP1A1 m1, m2, m3, and m4; CYP1B1 Arg(48)Gly, Ala(119)Ser, Val(432)Leu, and Asn(453)Ser; COMT Val(158)Met; UGT1A1 A(TA)nTAA; and SULT1A1 Arg(213)His polymorphisms. Unconditional logistic regression was used to calculate odds ratios (OR). Haplotypes were inferred and analyzed using models based on expectation-maximization with progressive ligation and Bayesian coalescence theory. CYP1B1 Leu(432) carriers were at increased risk of ovarian cancer, with an adjusted OR of 1.5 (95% confidence interval, 1.1-2.3) compared with Val(432) homozygotes. The most common CYP1B1 haplotype was Arg(48)-Ala(119)-Val(432)-Asn(453). All other haplotypes with frequencies >5% contained the Leu(432) allele. In diplotype analyses, relative to women homozygous for Arg(48)-Ala(119)-Val(432)-Asn(453), women with diplotypes containing at least one Leu(432) allele had adjusted ORs ranging from 1.3 to 2.2. Among women homozygous for COMT Met(158), carriers of CYP1B1 Leu(432) had a 2.6-fold increase in risk relative to CYP1B1 Val(432) homozygotes (95% confidence interval, 1.1-5.9). This latter result is opposite in direction from a similar analysis conducted by other investigators in a different study population. No association of ovarian cancer risk was observed with any of the other polymorphisms examined, either alone or in combination.
Holt
Sarah K
SK
Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, P. O. Box 19024 (M4-C308), Seattle, WA 98109-1024, USA. sholt@u.washington.edu
Rossing
Mary Anne
MA
Malone
Kathleen E
KE
Schwartz
Stephen M
SM
Weiss
Noel S
NS
Chen
Chu
C
D000328:Adult; D001741:Black or African American / Q000235:genetics; D000483:Alleles; D001499:Bayes Theorem; D016022:Case-Control Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004967:Estrogens / Q000235:genetics / Q000378:metabolism; D002393:Estrogens, Catechol / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011159:Population Surveillance; D012042:Registries; D012307:Risk Factors; D018426:SEER Program; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics
D004967:Estrogens; D002393:Estrogens, Catechol; D003577:Cytochrome P-450 Enzyme System