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Epidemiology and Prevention |
Department of Epidemiology [C. A. H., S. E. H., G. A. C., D. J. H., I. D. V.] and the Harvard Center for Cancer Prevention [C. A. H., D. J. H., I. D. V.], Harvard School of Public Health, Boston, Massachusetts 02115; Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115 [S. E. H., G. A. C., D. J. H., I. D. V.]; and the Department of Preventive Medicine, University of Southern California, Norris Comprehensive Cancer Center, Los Angeles, California 90089 [C. A. H.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Polymorphisms in genes involved in steroid hormone biosynthesis (CYP17, CYP19, and 17ß-HSD) and hormonal signaling (ER-
and PR) are currently being evaluated as genetic biomarkers for hormone-related diseases (5)
. One such candidate is a single (T to C) nucleotide change in the 5' region of CYP17, a gene encoding a cytochrome P450 enzyme, P450c17, involved in androgen biosynthesis (6)
. The bp change was thought to create a consensus Sp-1 binding site that may have an effect on the transcriptional regulation of CYP17. The variant allele, designated the A2 allele of CYP17, was found by Carey et al.
(6)
to be significantly associated with familial polycystic ovarian syndrome, a heterogeneous disorder associated with excess androgen production. On the basis of a potential role in altering steroid hormone metabolism, the A2 allele has been studied extensively among women in relation to breast cancer risk (Ref. 7
; reviewed in Ref. 5
). Positive associations have been reported but not supported in most studies.
We and others have provided preliminary results to support the hypothesis that this genetic variant may be involved in regulating steroid hormone biosynthesis among women (7 , 8) . Among healthy pre- and postmenopausal women, the A2/A2 CYP17 genotype has been associated with elevated levels of circulating androgens, estrogens and progesterone. In addition, it has been observed that women with the A2 allele are less likely to be current users of HRT, which suggests that genetic control of lifetime exposure to circulating hormone levels may influence HRT use (9) . Experimental evidence, however, does not support the idea that this nucleotide change creates an Sp-1 motif, as Kristensen et al. (10) did not observe Sp-1 binding to this polymorphic site. Whether other tissue-specific regulatory factors differentially bind to this motif remains unknown.
On the basis of the observed associations between the A2 allele of CYP17 and endogenous hormone levels, we selected CYP17 as a candidate gene to study in relation to endometrial cancer risk. Independent of a relationship between CYP17 genotype and the pattern of HRT use, we hypothesized that carriers of the A2 allele would be at increased risk of endometrial cancer. In a small preliminary multiethnic case-control study (11) , however, a significant inverse association was observed between the A2 allele and endometrial cancer risk among women taking estrogen replacement therapy (A1/A1 reference; A1/A2; OR, 0.39; 95% CI, 0.14–1.09; A2/A2; OR, 0 (no A2/A2 cases; P trend, 0.02).
We set out to determine whether CYP17 genotype is associated with risk of endometrial cancer among Caucasian women in a case-control study within the NHS cohort. We investigated potential interactions between endometrial cancer risk factors, CYP17 genotype, and endometrial cancer risk. We also further examined the relationship between CYP17 genotype and endogenous plasma steroid hormone levels among a relatively large sample of postmenopausal women.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In this study, we included both incident and prevalent endometrial cancer cases from the blood subcohort of the NHS. Eligible incident cases consisted of women with pathologically confirmed invasive endometrial cancer diagnosed anytime after blood collection up to June 1, 1996, with no previously diagnosed cancer except for nonmelanoma skin cancer. Prevalent cases were defined as having pathologically confirmed invasive endometrial cancer diagnosed between 1976 and the date of blood collection, with no previously diagnosed cancer except nonmelanoma skin cancer. Controls for both incident and prevalent cases were randomly selected participants who gave a blood sample, had not had a hysterectomy, and were free of diagnosed cancer (except nonmelanoma skin cancer) up to and including the interval in which the case was diagnosed. Controls were matched to cases (3:1 or 2:1) on year of birth, menopausal status at blood draw and diagnosis, and HRT status at blood draw (current versus not current users) as well as time of day, month, and fasting status at blood draw. The case-control study consists of 68 incident invasive endometrial cancer cases, 116 prevalent endometrial cancer cases, and 554 matched controls. The study samples for the plasma hormone analyses are composed of 165 postmenopausal control women from the NHS nested breast cancer case-control study 1996 follow-up cycle, in addition to the breast cancer controls from the 1989–1994 cycles (for a total of 469 women). None of the women had used HRT within 3 months of blood draw. The protocol was approved by the Committee on Human Subjects, Brigham and Women’s Hospital.
CYP17 Genotyping Assay.
CYP17 genotyping analysis was performed by the Taqman Allelic Discrimination method (12)
using the ABI 7700 Sequence Detection System (Applied Biosystems, Foster City, CA). This assay measures fluorescent intensity released from allele-specific fluorogenic probes and allows for high-throughput genotyping without post-PCR processing. A 97-bp fragment that included the T to C polymorphism was amplified in a 96-plate format using the following primers: 5'-AGGCCTCCTTGTGCCCTAGA-3' and 5'-GAGCCACGAGCTCCCACAT- 3'. The fluorescently labeled allele-specific probes are as follows: FAM 5'-CTTCTACTCCACTGCTGTCTTGCCTG-3' TAMARA and VIC 5'-CTTCTACTCCACCGCTGTCTTGCCT-3' TAMARA [bp change is highlighted (boldface and italic)]. Primers and probes were designed using Primer Express software (Applied Biosystems). Genomic DNA was used (40 ng per 25 µl of reaction) with 900 nM each primer, 100 nM FAM probe, 200 nM VIC probe, and 1x Taqman Universal PCR Master mix (Applied Biosystems). Amplification conditions were 2 min at 50°C, 10 min at 95°C, and 40 cycles of 15 s at 95°C, and 1 min at 63.5°C. The MspAI restriction enzyme and DNA sequencing were used to identify homozygous (CC and TT) controls required for this genotyping assay. Sequence Detection System software (Applied Biosystems) was used to determine CYP17 genotype. All of the genotyping was performed by laboratory personnel unaware of case-control status, and blinded quality control samples were inserted to validate genotyping identification procedures; concordance for blinded samples was 100%.
Hormone Assays.
Steroid hormone fractions of estradiol, estrone, estrone sulfate, testosterone, androstenedione, DHEA and DHEAS were measured in four separate batches. Methods for plasma hormone assays and information regarding laboratory precision and reproducibility have been published previously (13
, 14)
. Within-batch laboratory coefficients of variation were 
13.6%.
Exposure Data.
Information regarding endometrial cancer risk factors were obtained from the 1976 baseline questionnaire and were updated with subsequent biennial questionnaires and a questionnaire completed at the time of blood collection. Women were defined as postmenopausal at the time of blood collection if they reported having a bilateral oophorectomy or no menstrual cycle within the last 12 months before blood draw. Menopause status and postmenopausal hormone use, including the dose and duration of current use of conjugated estrogen or estrogen plus progestin, were updated until the date of diagnosis for cases and matched controls based on responses from the biennial questionnaires. First-degree family history of endometrial and colorectal cancer was assessed retrospectively from the 1996 follow-up questionnaire. Histopathological characteristics, such as subtype and differentiation status of epithelial carcinoma, were ascertained from medical records and used in case subgroup analyses when available.
Statistical Analysis.
McNemar’s test was used to evaluate differences in endometrial cancer risk factors and carrier status of the A2 allele of CYP17 between cases and controls. ORs and 95% CIs were calculated using conditional and unconditional logistic regression. In addition to the matching variables, we adjusted for endometrial cancer risk factors: BMI (kg/m2); weight gain since age 18 (<5, 5–19.9, or 
20 kg); age at menarche (<12, 12, 13, or >13 years); parity/age at first birth, (nulliparous; 1–2 children/age at first birth 24 years, 1–2/>24, 3/24, or 3/>24); duration of postmenopausal hormone use (never, past, or current <5 and 5 years); history of oral contraceptive use (ever/never); pack-years of smoking (never smoker, <30, or 30 pack-years); first-degree family history of endometrial cancer (yes/no); and first-degree family history of colorectal cancer (yes/no). Indicator variables for all three genotypes were created using the A1/A1 hypothesized low-risk genotype as the reference category in multivariate models. We used the 
2 test to evaluate whether CYP17 genotype was associated with HRT status among controls and, in case-case analyses, to examine associations between CYP17 genotype and the degree of differentiation of endometrial cancer. Interactions between genotype and endometrial cancer risk factors were evaluated by including interaction terms between genotype and risk factor variables in unconditional logistic regression models.
Linear regression was used to evaluate the association between genotype and circulating hormone levels among postmenopausal controls from the nested breast cancer case-control study within the NHS. Analyses were first conducted among the 165 controls matched to cases diagnosed during the 1996 follow-up cycle (1994 to 1996). A second analysis was then performed, which included these women and controls already included in the nested breast cancer case-control study on which we have previously examined the relationship between CYP17 genotype and plasma hormone levels (1989–1994; total n = 469). Differences in hormone levels between genotypes were evaluated with the A1/A1 genotype as the reference category. The natural logarithm of the plasma hormone values was used to reduce the skewness of the regression residuals. Hormone fractions were evaluated in multiple batches. All of the hormone fractions were not assayed in all of the women because of insufficient plasma. Within each batch, hormone values >3 interquartile ranges from the 75th percentile were treated as outliers and were excluded (estrone sulfate, n = 11; estrone, n = 3; estradiol, n = 7; testosterone, n = 2; androstenedione, n = 1; DHEA, n = 3; DHEAS, n = 1). We used the SAS statistical package for all analyses (15) .
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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2 = 0.38, df = 2, P = 0.83). Because we did not observe evidence of a "survivor bias," incident and prevalent cases were combined and analyzed together. There were 136 premenopausal and 564 postmenopausal women with mean ages of 49.5 (SD, 4.0) and 60.1 (SD, 6.7), respectively. Compared with controls, cases had a similar mean age at menarche (12.4 versus 12.5 years) and a greater BMI (28.0 versus 25.7 kg/m2). The proportion of women that ever used oral contraceptives was similar for both groups (36% versus 38%; P = 0.51). Cases were more likely to be nulliparous, 14% versus 9% (P = 0.03); to be current HRT users at diagnosis, 42% versus 30% (P = 0.01); and to have never smoked, 52% versus 42% (P = 0.02). The proportion of women with a first-degree family history of endometrial or colorectal cancer was also greater among the cases, 8.7% versus 3.6% (P = 0.01) and 22.8% versus 16.3% (P = 0.04), respectively. Self-reported major ethnicity/ancestry was similar between cases and controls (cases versus controls: Southern European, 17.9% versus 16.6%; Scandinavian, 9.0% versus 8.5%; and other Caucasian, 69.0% versus 72.1%). Asians, Hispanics, and African Americans comprised less than 1% of cases or controls.
The prevalence of the A2 allele among the controls was 40%, and identical to that observed among Caucasian women in our previous study (7)
. The distributions of CYP17 genotypes were in accordance with Hardy-Weinberg equilibrium among both cases (2 = 2.4, df = 1, P = 0.12) and controls (2 = 0.34, df = 1, P = 0.85). There was a significant difference in genotype frequencies between cases and controls (2 = 6.8, df = 2, P = 0.03; Table 1
). The A2 allele was underrepresented among women with endometrial cancer; 59% of the cases and 64% of controls carried at least one A2 allele (P = 0.16). Crude (not shown) and fully-adjusted ORs (Table 1)
were similar; therefore, we did not adjust for all matching variables and potential confounding risk factors to improve the precision of the relative risk estimates. Compared with the A1/A1 genotype, the ORs for women with the A1/A2 and A2/A2 genotypes were 0.89 (95% CI, 0.62–1.27) and 0.43 (95% CI, 0.23–0.80), respectively (Table 1)
. A significant gene-dosage effect was also suggested (P trend, 0.02). The adjusted OR for women carrying at least one A2 allele (A1/A2 and A2/A2 genotypes combined) was 0.78 (95% CI, 0.55–1.11). Associations were similar by menopausal status (Table 1)
. In case-only analyses, the A2 allele was nonsignificantly underrepresented among cases with poorly or moderately differentiated tumors compared with cases with well-differentiated tumors [38 (51%) of 75 versus 54 (60%) of 90; P = 0.23]. We did not observe an association between CYP17 genotype and HRT use; noncarriers of the A2 allele were not more likely to be current HRT users [percentage that were current HRT users by CYP17 genotype: controls: A1/A1, 41 (27%) of 152; A1/A2, 61 (30%) of 202; A2/A2, 22 (35%) of 63; cases: A1/A1, 20 (42%) of 48; A1/A2, 25 (42%) of 60; A2/A2, 6 (60%) of 10].
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0.3 mg/day, 0.625 mg/day, or 1.25 mg/day), because of the small number of cases that were current HRT users (n = 51). We were able to examine the potential interaction between CYP17 genotype and any HRT use at diagnosis (never, past, or current; Table 2
). We observed inverse associations between CYP17 genotype and endometrial cancer risk among both never and current HRT users. We observed a borderline significant inverse trend for the A2 allele among women who never used HRT (P trend, 0.08; Table 2
). Compared with the A1/A1 genotype, the OR for women with the A2/A2 genotype was 0.23 (95% CI, 0.05–1.06); however, there were only two A2/A2 cases in this stratum. There was no significant interaction between HRT status and CYP17 genotype (LRT, interaction P = 0.49). We did not observe evidence of effect modification or a statistical interaction between CYP17 genotype and BMI (LRT, interaction P = 0.28; Table 2
), oral contraceptive use (LRT, interaction P = 0.70), age at menarche (LRT, interaction P = 0.98), or parity (LRT, interaction P = 0.35).
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). Among women with this family history, a significant inverse association of CYP17 genotype was observed (P trend, 0.01), whereas no significant association was seen among women without this family history (P trend, 0.34).
In analyses of the relationship of genotype with plasma hormone levels among controls, we calculated least-squared geometric mean plasma steroid hormone levels for each genotype. We first evaluated the association among women selected as breast cancer controls during the 1996 follow-up cycle. Compared with women with the A1/A1 genotype, women with the A2/A2 genotype did not have significantly elevated levels of any estrogen or androgen hormone fraction [A2/A2 versus
A1/A1 genotype: estrone sulfate, -22.6% (P = 0.08); estrone, +3.1% (P = 0.75); estradiol, +1.5% (P = 0.91); testosterone, +5.3% (P = 0.64); androstenedione, +1.0% (P = 0.94); DHEA, +0.1% (P = 0.99); DHEAS, -9.5% (P = 0.55)]. Controls selected for hormone analyses in the 1996 cycle were similar to the controls previously included in our prior analysis (1989–1994) with respect to demographic characteristics (mean age, 61.5 versus 62.1 years; mean BMI, 26.8 versus 26.2 kg/m2; past HRT use: 32 versus 36%). In a combined analysis of all controls with hormone measurements from our previously published (7)
nested case-control study of breast cancer (1989–1996, n = 469), women with the A2/A2 genotype had marginally significantly higher levels of estrone (+10.9%, P = 0.05) and estradiol (+8.5%, P = 0.17; Table 3
). No positive associations were observed between the A2/A2 genotype and other hormone fractions.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The established risk factors for endometrial cancer are understood to act by altering chronic estrogen exposure unopposed by progesterone (3) . Likewise, the hypothesized mechanism through which genetic variation in CYP17 may influence endometrial cancer risk is by altering a woman’s lifetime exposure to endogenous steroid hormones. On the basis of the enzymatic steps catalyzed by CYP17, we would expect carriers of one or two A2 alleles to have elevated levels of downstream hormones (androgens and estrogens). We and others have provided preliminary results to support the proposed hypothesis that this genetic variant may be involved in regulating steroid hormone biosynthesis among women (7 , 8) . Feigelson et al. (8) initially reported premenopausal nulliparous women with the A2 allele to have higher levels of serum estradiol and progesterone measured during both phases of the menstrual cycle. Similarly, we observed postmenopausal women with the A2/A2 genotype to have elevated levels of circulating estrogens and androgens (versus A1/A1 genotype: estrone, +14.3%, P = 0.01; estradiol, +13.8%, P = 0.08; testosterone, +8.6%, P = 0.34; androstenedione, +17.1%, P = 0.06; DHEA, +14.4%, P = 0.02; DHEAS, +7.2%, P = 0.26; Ref. 7 ). In the present study, we reexamined CYP17 genotype as a predictor of circulating steroid hormone levels among postmenopausal women. Among the subset of postmenopausal breast cancer controls from the 1996 follow-up cycle, we did not observe women with the A2/A2 genotype to have significantly elevated levels of any steroid hormone fraction. In the combined analysis of previously published data and these new data, previous modest differences in hormone levels between CYP17 genotypes were substantially attenuated. The disparity in study results between this study and our previously published work are most likely attributable to chance and are not the result of substantial demographic or biological differences between the two postmenopausal control samples. Overall, these combined data provide only weak support for the prior hypothesis that this polymorphism regulates steroid hormone biosynthesis among postmenopausal women.
Feigelson et al. (8) initially detected premenopausal nulliparous women with the A2 allele to have significantly elevated levels of estradiol and progesterone (a precursor hormone to the steps catalyzed by CYP17). Compared with women with the A1/A1 genotype (n = 28), women with the A1/A2 (n = 45) and A2/A2 (n = 10) genotypes had 24 and 30% (P = 0.04) higher progesterone levels, respectively, measured at day 22 of the menstrual cycle. Although based on small numbers, these preliminary data suggest that premenopausal women with the A2 allele of CYP17 may have enhanced production of all steroid hormones because of heightened steroidogenesis. An upper limit of effective estrogen action on the rate of endometrial cell division has been suggested among premenopausal women; it has been argued that endometrial cell division is not dramatically increased by increases in estradiol concentration beyond the basal level produced during the follicular phase of the menstrual cycle (3) . Theoretically, premenopausal women with higher circulating progesterone levels even in the presence of higher estrogen levels may be at lower risk of endometrial cancer, which could potentially explain the inverse association that we observed between the A2 allele of CYP17 and endometrial cancer risk. Our CYP17 genotype-steroid hormone results among postmenopausal women do not provide strong support for genetic modulation of steroid hormone levels by CYP17 genotype. However, regulation of CYP17 expression via this polymorphism may differ between the ovaries and the adrenals, the predominant sites of steroid hormone production among premenopausal and postmenopausal women, respectively.
Although we did not observe significant interactions between CYP17 genotype and established endometrial cancer risk factors associated with estrogen exposure, we did observe suggestive evidence that the inverse association between the A2 allele and endometrial cancer risk was stronger among women who had never used HRT. These data suggest that the A2 allele of CYP17 may not play a role among women who are at a significantly increased risk of endometrial cancer because of long-time HRT use. However, we did not see a similar modification of risk with BMI; an inverse association with the A2 allele was actually stronger among women with greater BMI.
Little is known regarding genetic susceptibility to endometrial cancer. Endometrial cancer is a component of hereditary nonpolyposis colorectal cancer, which is caused by mutations in genes involved in DNA mismatch repair (MSH2, MLH1, PMS1, and PMS2; Ref. 16 ). Epidemiological studies have shown that women with a first-degree family history of colorectal and/or endometrial cancer are at significantly increased risk of endometrial cancer (17 , 18) . In our data, CYP17 genotype did not account for endometrial cancer risk associated with a first-degree family history of endometrial or colorectal cancer; the distribution of CYP17 alleles did not differ significantly among women with or without a family history of cancer overall, or among the controls. In addition, the effect estimates for family history and CYP17 genotype remained unchanged when both variables were included in multivariate models. However, we did observe a significant interaction between first-degree family history and CYP17 genotype, which appeared to be driven by the low frequency of the A2 allele among cases with a positive family history. A significant inverse association between the A2 allele and endometrial cancer risk was limited to women with a family history. Although preliminary, our results suggest that CYP17 genotype may be involved in modifying family history-associated endometrial cancer risk.
In view of the modest associations that we observed between CYP17 genotype and hormones levels, and the strong association observed between CYP17 genotype and endometrial cancer risk, the A1 or A2 alleles may be serving as markers of a functional variant in a nearby gene. However, this polymorphism may also be in linkage disequilibrium with an unidentified functional polymorphism in CYP17 that influences endometrial cancer risk, but does not produce detectable differences in circulating hormone levels among postmenopausal women. The relatively large sample size and the acquisition of risk factor information prospectively are strengths of this study. We did not observe evidence that endometrial cancer survival depended on CYP17 genotype, which allowed us to analyze incident and prevalent cases together and increase the statistical power of our study. One possible limitation was that ascertainment of first-degree family history of cancer was made retrospectively. Prevalent and incident cases may be more responsive to this question based on their personal cancer history; however, we would not expect their response to differ by CYP17 genotype. Larger studies are warranted to confirm these observations and to further examine interactions between CYP17 genotype and endometrial cancer risk factors. In summary, we provide evidence that the A2 allele of CYP17 is associated with decreased risk of endometrial cancer and that the association may be modified by first-degree family history of endometrial and colorectal cancer. However, CYP17 genotype has only modest effects, if any, on steroid hormone metabolism among postmenopausal women.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by NIH Grants CA82838 (to I. D. V.), CA87969, CA49449, and a grant from the American Cancer Society (RPG-00-061-01-CCE, to I. D. V.). 
2 To whom requests for reprints should be addressed, at Channing Laboratory, 181 Longwood Avenue, Boston, MA 02115.
3 The abbreviations used are: HRT, hormone replacement therapy; CYP17, cytochrome P450c17 gene; BMI, body mass index; DHEA, dehydroepiandrosterone; DHEAS, DHEA sulfate; OR, odds ratio; CI, confidence interval; LRT, likelihood ratio test; NHS, Nurses’ Health Study.
Received 12/ 8/00. Accepted 3/16/01.
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(CYP17) polymorphism is associated with serum estrogen and progesterone concentrations. Cancer Res., 58: 585-587, 1998. gene (CYP17) polymorphism predicts use of hormone replacement therapy. Cancer Res., 59: 3908-3910, 1999.This article has been cited by other articles:
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