Estrogen sulfation genes, hormone replacement therapy, and endometrial cancer risk.
BACKGROUND
Unopposed estrogen replacement therapy is associated with increased risk of endometrial cancer. To investigate the mechanism of this association, we evaluated whether risk of endometrial cancer was associated with the genotypes involved in steroid hormone metabolism and the duration of exogenous hormone use.


METHODS
A population-based case-control study in nine counties of the Philadelphia metropolitan area was undertaken with 502 case patients with endometrial cancer and 1326 age- and race-matched control subjects. Data regarding exogenous hormone use were obtained by interview, and genotypes of the genes COMT, CYP1A1, CYP1A2, CYP1B1, CYP3A4, PGR, SULT1A1, SULT1E1, and UGT1A1 were obtained by polymerase chain reaction techniques. Conditional logistic regression was used to examine the relationship among genotype, hormone use, and endometrial cancer risk.


RESULTS
Associations were observed between the risk of endometrial cancer and genotypes of the following steroid hormone metabolism genes: CYP1A1*2C (adjusted odds ratio [OR] = 1.68, 95% confidence interval [CI] = 1.08 to 2.61); SULT1A1*3 (adjusted OR = 0.51, 95% CI = 0.29 to 0.92); and the G --> A variant in the promoter of SULT1E1 at position -64 (adjusted OR = 1.45, 95% CI = 1.06 to 1.99). We observed a statistically significant interaction between estrogen replacement therapy use and SULT1A1*2 genotype: the SULT1A1*2 allele and long-term use of estrogen replacement therapy were associated with statistically significantly higher risk of endometrial cancer (adjusted OR = 3.85, 95% CI = 1.48 to 10.00) than that of the SULT1A1*2 allele and no estrogen replacement therapy use.


CONCLUSIONS
Among women with long-term use of estrogen replacement therapy or combined hormone replacement therapy, the risk of endometrial cancer may be associated with functionally relevant genotypes that regulate steroid hormone sulfation.
Rebbeck
Timothy R
TR
Department of Biostatistics and Epidemiology and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, 904 Blockley Hall, 423 Guardian Dr., Philadelphia, PA 19104-6021, USA. trebbeck@cceb.med.upenn.edu
Troxel
Andrea B
AB
Wang
Yiting
Y
Walker
Amy H
AH
Panossian
Saarene
S
Gallagher
Stephen
S
Shatalova
Ekaterina G
EG
Blanchard
Rebecca
R
Bunin
Greta
G
DeMichele
Angela
A
Rubin
Stephen C
SC
Baumgarten
Mona
M
Berlin
Michelle
M
Schinnar
Rita
R
Berlin
Jesse A
JA
Strom
Brian L
BL
D001189:Aryl Hydrocarbon Hydroxylases; D015239:Arylsulfotransferase / Q000235:genetics*; D016022:Case-Control Studies; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D016889:Endometrial Neoplasms / Q000201:enzymology / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics; D015914:Estrogen Replacement Therapy / Q000009:adverse effects* / Q000379:methods; D004967:Estrogens / Q000008:administration & dosage / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D016015:Logistic Models; D008875:Middle Aged; D016017:Odds Ratio; D015143:Philadelphia / Q000453:epidemiology; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011374:Progesterone / Q000008:administration & dosage / Q000378:metabolism; D015238:Sulfotransferases / Q000235:genetics; D000099148:UGT1A1 Enzyme
D001189:Aryl Hydrocarbon Hydroxylases; D015239:Arylsulfotransferase; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D004967:Estrogens; D014453:Glucuronosyltransferase; D011374:Progesterone; D015238:Sulfotransferases; D000099148:UGT1A1 Enzyme; C504573:CYP1A2 protein, human; C585496:CYP1B1 protein, human; C510163:CYP3A4 protein, human; C117544:SULT1A1 protein, human; C020122:estrone sulfotransferase