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Departments of Preventive Medicine [R. M-C., M. C. P., B. E. H.] and Urology [G. A. C.], University of Southern California Keck School of Medicine, Norris Comprehensive Cancer Center, Los Angeles, California 90033-0800; American Cancer Society, National Home Office, Atlanta, Georgia 30329-4251 [H. S. F.]; and Cancer Etiology Program, Cancer Research Center of Hawaii, University of Hawaii, Honolulu, 96813 Hawaii [L. N. K.]
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ABSTRACT |
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Introduction |
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One potential marker of endometrial cancer susceptibility is a
common variant in cytochrome P450 (CYP17), a gene that codes
for a key enzyme (cytochrome P450c17
) in a rate-limiting step of
estrogen biosynthesis (6)
. A single-bp polymorphism in the
5' untranslated region of CYP17 (27 bp downstream from the
transcription start site) has been used to identify two alleles,
T (formerly designated as A1) and C (formerly
designated as A2). Of relevance to endometrial cancer risk, at least
two studies have found that the C allele is associated with
elevated levels of circulating estrogens in pre- and postmenopausal
women (7
, 8)
. Furthermore, we found that CYP17
is closely associated with patterns of postmenopausal hormone
replacement therapy, such that women who carry two copies of the
C allele are about half as likely as women with the
T allele to be current users of hormone replacement therapy
(9)
.
In the current study, we examined the association between endometrial cancer risk and ERT (without progestins) by CYP17 genotype using cases and controls from a MEC in Hawaii and Los Angeles, California.
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Materials and Methods |
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This case cohort study included 51 incident cases of endometrial cancer and 391 randomly selected MEC controls who reported never taking ERT or exclusively taking estrogens without progestins (ERT). Both cases and controls were postmenopausal women ages 60 years and over at the time of blood draw from the four primary cohort racial/ethnic groups (African American, Japanese, Latina, and non-Latina white). Cases and potential controls were contacted by letter and phone call, followed by a home visit to collect a blood specimen. Blood draw was completed in the morning, typically at the person’s home, after informed consent was obtained. Participation rates for providing a blood sample on request were 74% for cancer cases and 66% for cohort controls. Case ascertainment was completed through the Surveillance, Epidemiology and End Results program in Los Angeles and Hawaii. Controls had no history of endometrial, breast, or ovarian cancer and reported no prior hysterectomy.
Genotyping.
DNA was purified from buffy coats of peripheral blood samples.
The CYP17 assay has been described previously
(11)
. A PCR fragment containing the bp change was
generated using the following primers: CYP-1, 5-CATTCGCACTCTGGAGTC-3;
and CYP-2, 5-AGGCTCTTGGGGTACTTG-3. PCR reactions were carried out in
25-µl aliquots containing about 50 ng of genomic DNA, 50 pmol of each
primer, 1x reaction buffer, 100 µM
deoxynucleotide triphosphates, and 1 unit of Taq polymerase
(Pharmacia). The amplification was performed for 30 cycles of
denaturation at 94°C for 1 min, annealing at 57°C for 1 min, and
extension at 72°C for 1 min. An initial denaturation step of 5 min at
94°C and a final extension at 72°C for 5 min were used. The PCR
products were digested for 3 h at 37°C using MspAI,
separated by agarose gel electrophoresis, and stained with ethidium
bromide to identify the bp change.
Statistical Analysis.
The relative risk of endometrial cancer was calculated for ever use
versus never use of ERT by CYP17 genotype
(TT, TC, and CC). Logistic regression,
conditional on CYP17 genotype, was used to calculate summary
and stratum-specific ORs and 95% CIs controlling for age (quartiles)
and racial/ethnic group as categorical variables in the model.
Controlling for weight as a categorical variable (quartiles) did not
change the effect estimates. Two sided Ps were calculated to
test associations between ERT and endometrial cancer risk for summary
and genotype-specific estimates. A one-sided test for homogeneity
across strata of CYP17 was calculated to test whether women
with the TT genotype were significantly more likely to
develop endometrial cancer while taking ERT than women with the
TC or CC genotypes.
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Results |
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Women who reported ever taking ERT in this study were more than twice
as likely to develop endometrial cancer than women who never took ERT
(Table 1)
. Among these women, the risk of endometrial cancer was significantly
elevated for women with the TT genotype (OR, 4.10) but was
only slightly elevated for women with the TC or
CC genotype (OR, 1.31). Using a one-sided test for
homogeneity across strata, women with the TT genotype were
at significantly higher risk of developing endometrial cancer with ERT
use than women with the TC or CC genotypes. The
effect of the T allele in never ERT users was small (data
not shown) and did not reach statistical significance after adjustment
for age and racial/ethnic group (OR for the TT versus
CC genotype, 1.30; 95% CI, 0.39–4.26).
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Discussion |
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One potential explanation of the difference in risk for endometrial cancer by CYP17 genotype for postmenopausal ERT users may be due to individual differences in estrogen binding and metabolism, such that the T allele of the T27C marker may distinguish women whose overall estrogen biosynthetic and metabolism systems are down-regulated (or up-regulated for the C allele). Based on normal, circulating estrogen levels by CYP17 genotype (7 , 8) , women with the T allele may bind and eliminate circulating estrogens less efficiently than women with the C allele. If the efficiency of a woman’s metabolic system to process E1 differs according to normal endogenous E1 production levels, the addition of a similar dose of postmenopausal ERT may have a greater effect on women with the T allele (who would normally transport and metabolize relatively low endogenous levels of E1) compared with women with the C variant. However, to accurately interpret these findings, more testing on circulating levels of endogenous estrogens is necessary to see whether estrogen levels are correlated with CYP17 genotype among women taking a standard dose of ERT.
The relationship between risk of endometrial cancer and use of estrogen and progestin replacement therapy is extremely important, given findings that estrogen and progestin replacement therapy is protective for endometrial cancer risk but may increase a woman’s risk of breast cancer (13) . The risks and benefits of prescribing unopposed estrogen or estrogens in combination with progestins for women in relation to their risk for endometrial and breast cancer would be better clarified if markers of disease and individual responsiveness to exogenous hormones were available. The current findings suggest that CYP17 or other variants in the estrogen biosynthesis or metabolism pathway may be potential markers of endometrial cancer susceptibility due to ERT. The current findings are based on small numbers and need to be replicated in larger epidemiological studies. Although the functional relevance of the CYP17 gene is still unproven, these preliminary data suggest that CYP17 could be a marker of up-regulated estrogen biosynthesis and metabolism that may be of utility in studies of endometrial cancer risk.
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FOOTNOTES |
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1 Supported by National Cancer Institute Grants
CA63464 and CA54281. 
2 To whom requests for reprints should be
addressed, at University of Southern California/Norris Comprehensive
Cancer Center, 1441 Eastlake Avenue, MS/44, Los Angeles, CA 90033-0800.
Phone: (323) 865-0413; Fax: (323) 865-0127.
3 The abbreviations used are: ERT, estrogen
replacement therapy; OR, odds ratio; CI, confidence interval; MEC,
multiethnic cohort; E1, estrone.
Received 10/17/00. Accepted 12/15/00.
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