Abstract
UDP-glucuronosyltransferases (UGTs) are a family of phase II metabolizing enzymes involved in glucuronic acid conjugation of sex-steroid hormones. UGT1A1 and UGT2B7 are expressed in the uterus and involved in conjugation and elimination of estrogens. Chronic exposure to estrogens is associated with endometrial cancer. Functional polymorphisms have been identified in UGT1A1 and UGT2B7. We hypothesized that these variants may be associated with endometrial cancer risk. We conducted a case-control study nested within the Nurses’ Health Study and Women’s Health Study to investigate the associations between five polymorphisms and endometrial cancer risk using 593 invasive endometrial cancer cases and 1,545 controls. We did observe the suggestion of an inverse association with homozygote variant carriers of UGT1A1*28 and endometrial cancer risk. We did not observe significant associations between individual SNPs and UGT1A1 haplotypes and endometrial cancer risk. Our data suggests that these UGT polymorphisms do not contribute significantly to endometrial cancer risk.
Keywords: endometrial cancer, polymorphisms, genetics, UGT
Introduction
UDP-glucuronosyltransferases (UGTs) are involved in glucuronidation, a final inactivation and elimination process for endogenous and exogenous molecules such as drugs, pollutants, and estrogens (1). Data demonstrate that estrogens have a dual role in endometrial carcinogenesis; as a hormone that promotes cell proliferation and as a procarcinogen (2). Glucuronidation reduces the biological activity of estrogens and presumably blocks the genotoxic 4-hydroxy-estrogen metabolite oxidation to quinone estrogens reducing their mutagenic potential (2).
UGT1A1 is expressed in the uterus and is involved in the inactivation of estradiol and its oxidized metabolites with a preference for the glucuronidation of 2-hydroxyestrogen (3–5). A promoter polymorphism, UGT1A1*28, is characterized by a TA insertion in the regulatory TATA box of the promoter and decreases gene expression compared to the major UGT1A1*1 allele (6, 7). Additional polymorphisms, UGT1A1 −3279 T>G and UGT1A1 −3156 G>A, have also been identified (8, 9). Variability in the expression of the UGT1A1 protein might lead to differences in estrogen biotransformation and explain interindividual differences in endometrial cancer risk. Our previous findings support a role for UGT1A1 in estrogen metabolism in the uterus (5).
UGT2B7, also expressed in the uterus, mainly catalyzes the glucuronidation of 4-hydroxyestrogens (4). A C>T transition at nucleotide 802 results in an H268Y amino acid change (10),and a promoter polymorphism, −79G>A, decreases the basal transcriptional activity of the UGT2B7 promoter (11, 12).
We hypothesized that the polymorphic activity or expression of estrogen-metabolizing UGTs may alter the local concentration of estrogen metabolites favoring an imbalance of estradiol and its metabolites and therefore modify endometrial cancer risk. We conducted a nested case-control study within the Nurses’ Health Study (NHS) and the Women’s Health Study (WHS) to investigate the associations between these five polymorphisms and endometrial cancer risk.
Materials and Methods
The NHS is a prospective cohort study of 121,700 women enrolled in 1976. During 1989–90, blood samples were collected from 32,826 women. In 2000–2002, buccal cell samples were collected from 32,883 women who had not provided a blood sample. Cases were women with pathologically confirmed invasive endometrial cancer diagnosed after cohort inception and prior to June 1, 2000. Controls were randomly selected from participants who had not had a hysterectomy and were free of diagnosed cancer. Controls were matched to cases according to age, menopausal status, postmenopausal hormone use, and type of biospecimen. Completion of the self-administered questionnaire was considered to imply informed consent, and written informed consent was received for the biospecimen samples.
The WHS is a completed randomized, double-blind, placebo-controlled trial investigating the benefits and risks of aspirin and vitamin E in the primary prevention of cancer and cardiovascular disease among 39,876 female health professionals, with enrollment beginning in April 1993. Blood samples were collected from 28,345 women. WHS cases consisted of women with confirmed endometrial cancer diagnosed after blood collection and prior to June 1, 2002. Controls were randomly selected participants who had given a blood sample, had not had a hysterectomy, and were free of diagnosed cancer. Controls were matched according to age, menopausal status and postmenopausal hormone use. Written informed consent was obtained from all women before entry into the trial. Each study protocol was approved by the Committee on Use of Human Subjects of the Brigham and Women’s Hospital, Boston, MA.
Genotyping was performed at the Dana Farber/Harvard Cancer Center High Throughput Genotyping Core and at Laval University. The UGT1A1 dinucleotide insertion/deletion was genotyped using a previously described method (13). The UGT1A1 −3279 T>G, UGT1A1 −3156 G>A, and the UGT2B7 −79 G>A polymorphisms were genotyped by the 5’ nuclease assay (Taqman). The UGT2B7 H268Y polymorphism was genotyped by direct sequencing of PCR products. Laboratory personnel were blinded to case-control status, and 5% blinded quality control samples were inserted to validate genotyping procedures; concordance for blinded samples was 100%.
Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of endometrial cancer. In addition to the matching factors, analyses were adjusted for body mass index (BMI; kg/m2); age at menarche; parity/age at first birth; smoking status; menopausal status; age at menopause; postmenopausal hormone use; and first-degree family history of colorectal cancer. We created indicator variables for the genotypes using individuals homozygous for the most common allele as the reference. Gene dosage effects were modeled by assigning the values of 0, 1, and 2 to a genotype trend variable according to the subject’s number of variant alleles. Tests of heterogeneity were conducted to determine the appropriateness of pooling the two datasets. We used the DerSimonian and Laird random effects model to combine results from the cohorts after testing for heterogeneity. We combined heterozygote and homozygote variants in the interaction analyses. For exploratory analyses, we tested pairwise statistical interactions between the different genotypes in logistic regression models by using a likelihood-ratio test (LRT) to compare nested models that included terms for all combinations of the genotypes to models with indicator variables for main effects only. To test statistical interactions between the UGT genotypes and environmental exposures in the regression models, we used a LRT to compare nested models that included terms for all combinations of genotypes and levels of environmental exposures to models with indicator variables for the main effects only.. All p-values were two-sided. All analyses were restricted to Caucasians, and numbers may vary for the different analyses due to missing genotype data.
We employed a haplotype-based approach for UGT1A1 and estimated haplotype frequencies and haplotype-specific ORs using an expectation-substitution method to account for haplotype uncertainty given unphased genotyping data. We performed a global test of significance to determine whether haplotype frequencies differed between cases and controls. Conditional logistic regression was used to calculate adjusted ORs and 95% CIs for haplotype associations with endometrial cancer risk, using the most common haplotype as the reference category.
Results
We have 456 NHS endometrial cancer cases and 1,134 matched controls and 137 WHS cases and 411 matched controls for a total sample size of 593 cases and 1,545 matched controls (Table 1). Allele frequencies were similar to previous reports in Caucasian populations (5, 14, 15), and genotypes were in accordance with Hardy-Weinberg equilibrium. All p-values for the tests of heterogeneity comparing the NHS and WHS results were >0.05. We did not observe any statistically significant associations with the five polymorphisms in UGT1A1 and UGT2B7 and endometrial cancer risk (Table 2–Table 3), nor did we detect any effect modification.
Table 1.
Descriptive characteristics of endometrial cancer cases and controls in the NHS and WHS1
| Variables | NHS cases (n=456) |
NHS controls (n=1134) |
WHS cases (n=137) |
WHS controls (n=411) |
|---|---|---|---|---|
| Age at biospecimen collection, mean (SD) | 59.4 (6.7) | 59.6 (6.6) | 56.9 (7.3) | 57.0 (7.3) |
| Age at menarche, mean (SD) | 12.5 (1.4) | 12.6 (1.4) | 12.4 (1.3) | 12.5 (1.4) |
| Menopausal status at diagnosis, n (%) | ||||
| Premenopausal | 90 (19.2) | 161 (14.1) | 15 (11.5) | 99 (24.1) |
| Postmenopausal | 371 (78.9) | 955 (83.3) | 110 (84.6) | 285 (69.3) |
| Dubious/missing | 9 (1.9) | 30 (2.6) | 5 (3.9) | 27 (6.6) |
| PMH use at diagnosis2, n (%) | ||||
| Never | 132 (37.9) | 411 (45.6) | 49 (36.8) | 227 (55.2) |
| Former | 66 (19.0) | 216 (24.0) | 26 (19.6) | 33 (8.0) |
| Current | 150 (43.1) | 274 (30.4) | 58 (43.6) | 151 (36.7) |
| Age at menopause, mean (SD) | 50.3 (4.3) | 49.7 (4.0) | 49.6 (4.5) | 49.5 (4.3) |
| BMI at diagnosis, kg/m, mean (SD) | 28.3 (7.0) | 25.8 (5.0) | 29.0 (7.3) | 25.6 (4.4) |
| Parity3, mean (SD) | 3.1 (1.4) | 3.3 (1.5) | 2.7 (1.3) | 2.8 (1.4) |
| Ethnicity/ancestry, n (%) | ||||
| Caucasian/Non-Hispanic | 434 (96.4) | 1057 (95.3) | 130 (96.3) | 391 (95.8) |
| African-American/Black | 1 (0.22) | 8 (0.72) | 2 (1.5) | 5 (1.2) |
| Asian/Pacific Islander | 3 (0.67) | 7 (0.63) | 1 (0.74) | 5 (1.2) |
| American Indian | 0 (0.0) | 9 (0.81) | 0 (0.0) | 2 (0.49) |
| Other | 12 (2.7) | 28 (2.5) | 2 (1.5) | 5 (1.2) |
| First-degree family history of colon cancer, n (%) | 99 (21.1) | 211 (18.4) | 9 (6.6) | 44 (10.7) |
| Ever OC use, n (%) | 176 (37.5) | 470 (41.0) | 70 (51.1) | 254 (62.1) |
| Smoking status at diagnosis, n (%) | ||||
| Never | 236 (50.9) | 502 (44.2) | 71 (55.5) | 206 (50.1) |
| Former | 169 (36.4) | 447 (39.3) | 36 (28.1) | 158 (38.4) |
| Current | 59 (12.7) | 188 (16.5) | 21 (16.4) | 47 (11.4) |
Numbers may not sum to total due to missing values
Among postmenopausal women
Among parous women
Table 2.
UGT1A1 polymorphisms and endometrial cancer risk in WHS and NHS1
| UGT1A1 polymorphisms | Cases, n (%) | Controls, n (%) | OR (95% CI)2 | Adjusted OR (95% CI)3 |
|---|---|---|---|---|
| UGT1A1 TA repeat | ||||
| *1/*1 | 247 (45.6) | 628 (45.2) | 1.00 | 1.00 |
| *1/*28 | 245 (45.2) | 596 (42.9) | 1.08 (0.82, 1.43) | 1.16 (0.74, 1.83) |
| *28/ *28 | 50 (9.2) | 166 (11.9) | 0.76 (0.51, 1.14) | 0.66 (0.44, 0.99) |
| P = 0.73 | P = 0.24 | |||
| *28 carriers | 295 (54.4) | 762 (54.8) | 1.03 (0.75, 1.42) | 1.05 (0.71, 1.56) |
| UGT1A1 −3156 G/A | ||||
| G/G | 239 (48.1) | 629 (48.7) | 1.00 | 1.00 |
| G/A | 219 (44.1) | 535 (41.4) | 1.06 (0.85, 1.33) | 1.13 (0.81, 1.56) |
| A/A | 39 (7.9) | 128 (9.9) | 0.85 (0.55, 1.31) | 0.68 (0.43, 1.08) |
| P = 0.97 | P = 0.46 | |||
| A carriers | 258 (51.9) | 663 (51.3) | 1.04 (0.80, 1.35) | 1.04 (0.77, 1.42) |
| UGT1A1 −3279 G/T | ||||
| G/G | 164 (32.4) | 418 (32.1) | 1.00 | 1.00 |
| G/T | 243 (47.9) | 599 (46.0) | 1.02 (0.80, 1.30) | 1.07 (0.81, 1.41) |
| T/T | 100 (19.7) | 285 (21.9) | 0.91 (0.63, 1.31) | 0.97 (0.61, 1.57) |
| P = 0.56 | P = 0.96 | |||
| T carriers | 343 (67.7) | 884 (67.9) | 0.98 (0.77, 1.23) | 1.03 (0.79, 1.34) |
The number of participants does not sum to total women because of missing data on genotype.
Conditional logistic regression model conditioned on the strata defined by the matching variables: age, menopausal status and postmenopausal hormone use at blood collection, date of blood draw, time of blood draw, and fasting status at blood draw.
Conditional logistic regression model conditioned on the strata defined by the matching variables and body mass index at diagnosis, age at menarche, age at menopause, menopausal status and postmenopausal hormone use at diagnosis, first-degree family history of colorectal cancer, parity, age at first birth, and smoking status.
Table 3.
UGT2B7 polymorphisms and endometrial cancer risk in WHS and NHS1
| UGT2B7 polymorphisms | Cases, n (%) | Controls, n (%) | OR (95% CI)2 | Adjusted OR (95% CI)3 |
|---|---|---|---|---|
| UGT2B7 −79 G/A | ||||
| G/G | 479 (93.4) | 1256 (93.7) | 1.00 | 1.00 |
| G/A | 33 (6.4) | 85 (6.3) | -- | -- |
| A/A | 1 (0.20) | 0 | -- | -- |
| A carriers | 34 (6.6) | 85 (6.3) | 0.96 (0.63, 1.48) | 1.07 (0.67, 1.72) |
| UGT2B7 H268 Y | ||||
| H268/H268 | 134 (25.0) | 328 (23.5) | 1.00 | 1.00 |
| H268/Y268 | 243 (45.5) | 679 (48.6) | 0.84 (0.65, 1.08) | 0.87 (0.65, 1.15) |
| Y268/Y268 | 157 (29.4) | 390 (27.9) | 0.96 (0.72, 1.27) | 0.93 (0.67, 1.27) |
| P = 0.84 | P = 0.69 | |||
| Y268 carriers | 400 (74.9) | 1069 (76.5) | 0.88 (0.69, 1.12) | 0.89 (0.68, 1.16) |
The number of participants does not sum to total women because of missing data on genotype.
Conditional logistic regression model conditioned on the strata defined by the matching variables: age, menopausal status and postmenopausal hormone use at blood collection, date of blood draw, time of blood draw, and fasting status at blood draw.
Conditional logistic regression model conditioned on the strata defined by the matching variables and body mass index at diagnosis, age at menarche, age at menopause, menopausal status and postmenopausal hormone use at diagnosis, first-degree family history of colorectal cancer, parity, age at first birth, and smoking status.
We identified four UGT1A1 common promoter haplotypes. The global test of significance was not statistically significant (χ2 = 2.81, df = 3, P = 0.44) (Table 4). However, a haplotype analysis that uses only these three promoter polymorphisms may not represent the complete genetic variation across the entire gene.
Table 4.
UGT1A1 promoter haplotypes and endometrial cancer risk in WHS and NHS
| UGT1A1 haplotype | −3279 G/T | −3156 G/A | TA repeat number | Cases (%) | Controls (%) | OR (95% CI)1 | Adjusted OR (95% CI)2 |
|---|---|---|---|---|---|---|---|
| I | T | G | 6 | 56.5 | 54.8 | 1.00 | 1.00 |
| II | G | A | 7 | 29.0 | 29.5 | 0.97 (0.82, 1.13) | 0.95 (0.80, 1.13) |
| III | G | G | 6 | 10.5 | 11.4 | 0.83 (0.65, 1.07) | 0.91 (0.69, 1.20) |
| IV | G | G | 7 | 3.1 | 3.5 | 0.86 (0.57, 1.32) | 0.91 (0.57, 1.44) |
Conditional logistic regression model conditioned on the strata defined by the matching variables: age, menopausal status and postmenopausal hormone use at blood collection, date of blood draw, time of blood draw, and fasting status at blood draw.
Conditional logistic regression model conditioned on the strata defined by the matching variables and body mass index at diagnosis, age at menarche, age at menopause, menopausal status and postmenopausal hormone use at diagnosis, first-degree family history of colorectal cancer, parity, age at first birth, and smoking status.
Discussion
This study was initiated to understand the significance of UGT1A1 and UGT2B7 genetic variants on the risk of endometrial cancer. The UGT family of enzymes catalyzes the glucuronidation of sex steroid hormones, which play a significant role in endometrial carcinogenesis. Polymorphisms in these two UGT genes have been identified, and studies have revealed differences in the functional activities and transcriptional levels of the genetic variants.
Estrogens and progesterone are important determinants of endometrial cancer risk, and many risk factors associated with endometrial cancer increase estrogen exposure and decrease progesterone production. Estradiol and its metabolites may be eliminated to inactive glucuronides by specific UGT proteins (4).
We observed no significant associations between the UGT1A1 polymorphisms and endometrial cancer risk. Previous work has shown that the variant alleles are associated with decreased transcription and protein expression levels reducing the conjugation of specific UGT1A1 substrates particularly 2-hydroxylated and 2-methoxylated metabolites of estradiol and estrone (16). We hypothesized that these polymorphisms would reduce endometrial cancer risk by favoring the accumulation of the protective 2-methyoxyestrogen and its precursors. However, it is also possible that estradiol exposure is modified by UGT1A1 genotype since this enzyme is also active for primary estrogen (4). Rebbeck et al. (15) and Deming et al. (17) found no significant association between the UGT1A1*28 allele and endometrial cancer risk in American or Chinese women. No studies have investigated the associations between the UGT1A1 −3279 T>G and UGT1A1 −3156 G>A polymorphisms and endometrial cancer risk.
We observed no associations between the UGT2B7 polymorphisms and endometrial cancer risk. Compared to the H268 allele, the Y268 variant allele is associated with a higher or similar capacity to conjugate carcinogenic estrogens, and the UGT2B7 −79 A variant allele decreases transcription (3, 11, 12). We hypothesized that the Y268 allele present in approximately 50% of Caucasians would be inversely associated with risk by favoring the inactivation of the mutagenic 4-hydroxyestrogen metabolites. The low transcription −79A variation is in strong linkage disequilibrium with the high activity UGT2B7 Y268 allele, therefore this haplotype which occurs in 5% of the Caucasian population would presumably not affect the risk. No studies have investigated the associations between these two UGT2B7 polymorphisms and endometrial cancer risk.
We chose functionally relevant SNPs in UGT1A1 and UGT2B7 that were more likely to produce significant effects on hormone levels and endometrial cancer risk. This is the first study to investigate the associations between the UGT1A1 and UGT2B7 genetic variants and endometrial cancer risk and the largest case-control study to utilize prospectively collected covariate information. We found that the UGT1A1*28, UGT1A1 −3279 T>G, UGT1A1 −3156 G>A, UGT2B7 H268Y and UGT2B7 −79 G>A polymorphisms are not associated with endometrial cancer susceptibility, although our power was limited. Additional larger possibly consortium studies with thousands of cases and matched controls are needed to determine the significance of additional UGT polymorphisms in UGT2B7 and UGT1A1 and endometrial cancer risk. Other locally expressed UGT enzymes may also likely play a role in endometrial cancer susceptibility and deserve further investigation.
Acknowledgements
We thank H. Ranu, P. Soule, and M. Chown for assistance, and we thank the participants in the Nurses’ Health Study and the Women’s Health Study for their dedication and commitment. This work is supported by National Institute of Health Grants: CA87969, CA49449, CA82838, CA047988, HL043851, NICHD K12 HD051959-01, a grant from the American Cancer Society: RSG-00-061-04-CCE, and a grant from the Canadian Institutes of Health Research (CIHR MOP-68964, C.G.). J.L. is recipient of a studentship award from CIHR.CG is a holder of the Canada Research Chair in Pharmacogenomics.
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