Progesterone receptor promoter +331A polymorphism is associated with a reduced risk of endometrioid and clear cell ovarian cancers.
OBJECTIVE
The progestagenic milieu of pregnancy and oral contraceptive use is protective against epithelial ovarian cancer. A functional single nucleotide polymorphism in the promoter of the progesterone receptor (+331A) alters the relative abundance of the A and B isoforms and has been associated with an increased risk of endometrial and breast cancer. In this study, we sought to determine whether this polymorphism affects ovarian cancer risk.


METHODS
The +331G/A polymorphism was genotyped in a population-based, case-control study from North Carolina that included 942 Caucasian subjects (438 cases, 504 controls) and in a confirmatory group from Australia (535 cases, 298 controls). Logistic regression analysis was used to calculate age-adjusted odds ratios (OR).


RESULTS
There was a suggestion of a protective effect of the +331A allele (AA or GA) against ovarian cancer in the North Carolina study [OR, 0.72; 95% confidence interval (95% CI), 0.47-1.10]. Examination of genotype frequencies by histologic type revealed that this was due to a decreased risk of endometrioid and clear cell cancers (OR, 0.30; 95% CI, 0.09-0.97). Similarly, in the Australian study, there was a nonsignificant decrease in the risk of ovarian cancer among those with the +331A allele (OR, 0.83; 95% CI, 0.51-1.35) that was strongest in the endometrioid/clear cell group (OR, 0.60; 95% CI, 0.24-1.44). In the combined U.S.-Australian data that included 174 endometrioid/clear cell cases (166 invasive, 8 borderline), the +331A allele was significantly associated with protection against this subset of ovarian cancers (OR, 0.46; 95% CI, 0.23-0.92). Preliminary evidence of a protective effect of the +331A allele against endometriosis was also noted in control subjects (OR, 0.19; 95% CI, 0.03-1.38).


CONCLUSIONS
These findings suggest that the +331G/A progesterone receptor promoter polymorphism may modify the molecular epidemiologic pathway that encompasses both the development of endometriosis and its subsequent transformation into endometrioid/clear cell ovarian cancer.
Berchuck
Andrew
A
Division of Gynecologic Oncology, Duke University Medical Center, Box 3079, Durham, NC 27710, USA. berch001@mc.duke.edu
Schildkraut
Joellen M
JM
Wenham
Robert M
RM
Calingaert
Brian
B
Ali
Shazia
S
Henriott
Amy
A
Halabi
Susan
S
Rodriguez
Gustavo C
GC
Gertig
Dorota
D
Purdie
David M
DM
Kelemen
Livia
L
Spurdle
Amanda B
AB
Marks
Jeffrey
J
Chenevix-Trench
Georgia
G
D018262:Adenocarcinoma, Clear Cell / Q000235:genetics* / Q000517:prevention & control*; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000517:prevention & control*; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011980:Receptors, Progesterone / Q000235:genetics*; D012307:Risk Factors
D011980:Receptors, Progesterone