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Carcinogenesis Advance Access originally published online on June 15, 2006
Carcinogenesis 2006 27(11):2281-2285; doi:10.1093/carcin/bgl099
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Polymorphisms in O6-methylguanine DNA methyltransferase and endometrial cancer risk

Jiali Han1,3,*, Susan E. Hankinson1,2 and Immaculata De Vivo1,2,3

1 Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School 181 Longwood Avenue, Boston, MA 02115, USA
2 Department of Epidemiology 665 Huntington Avenue, Boston, MA 02115, USA
3 The Program in Molecular and Genetic Epidemiology, Harvard School of Public Health 665 Huntington Avenue, Boston, MA 02115, USA

*To whom correspondence should be addressed. Tel: +1 617 525 2098; Email: jiali.han{at}channing.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Cigarette smoking is inversely associated with endometrial cancer risk. Smoking is proposed to decrease risk, in large part, through its anti-estrogenic effects in the uterus. In addition, cigarette smoke is a major source of alkylation damage. The O6-methylguanine DNA methyltransferase (MGMT) gene is responsible for repairing alkylation DNA damage and also has a role in inhibiting estrogen receptor-mediated cell proliferation. Because of MGMT's dual functions, it is a strong candidate gene for endometrial cancer. We assessed the two functional polymorphisms, the Leu84Phe and Ile143Val, in relation to endometrial cancer risk in a nested case–control study within the Nurses’ Health Study (cases = 456, controls = 1134). Compared with the 84Leu/Leu genotype, the Phe carriers had a significantly decreased risk of endometrial cancer [odds ratio (OR), 0.72; 95% confidence interval (CI), 0.53–0.96]. We did not observe an association between the Ile143Val polymorphism and endometrial cancer risk overall. We observed a significant multiplicative interaction between the Ile143Val polymorphism and pack-years of smoking on endometrial cancer risk (P, interaction, 0.04); the inverse association of pack-years with endometrial cancer risk was limited to the 143Val carriers (P, trend, 0.01). Compared with women who had the Ile/Ile genotype and never smoked, the 143Val carriers who had >30 pack-years of smoking had a significantly decreased risk of endometrial cancer (OR, 0.41; 95%CI, 0.19–0.86). These data suggest that these two polymorphisms may influence endometrial cancer risk.

Abbreviations: BMI, body mass index; CI, confidence interval; ER, estrogen receptor; MGMT, O6-methylguanine DNA methyltransferase; OR, odds ratio


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
The predominant risk factor for endometrial cancer is exposure to estrogens, endogenous or exogenous, unopposed by progesterone. Risk factors known to increase risk include early onset of menarche, late menopause, nulliparity, higher body mass index (BMI) and postmenopausal hormone use, whereas cigarette smoking is inversely associated with endometrial cancer risk (1). The biological mechanism for the inverse association is thought to be multifactorial. A major hypothesis is that smoking has an anti-estrogenic effect in the uterus (1–3). However, the inverse association may not be limited only to current smokers; several studies have observed a similar inverse association among past smokers (1,4–6). In addition, pack-years of smoking, which is a measure of dose and duration, before the age of 30 was also inversely associated with endometrial cancer risk (1). These data suggest that the effect of smoking on endometrial cancer risk may extend beyond an immediate anti-estrogenic effect.

Cigarette smoking is a major source of alkylation damage. The O6-methylguanine DNA methyltransferase (MGMT) gene is responsible for repairing alkylation DNA damage. The MGMT gene encodes a direct reversal DNA repair protein that removes alkyl or methyl adducts from the O6 position of guanine to an internal cysteine residue at codon 145 of the protein (7,8). MGMT prevents mutagenesis and malignant transformation, and also provides resistance to chemotherapy with alkylating agents among cancer patients (9,10). In addition, it has been shown that upon the repair of damage, MGMT alters its conformation to expose its LXXLL motif and binds estrogen receptor (ER), thus blocking ER from binding transcription coactivators containing the same motif (11). Therefore, MGMT also inhibits ER-mediated cell proliferation. Both of these MGMT functions may play a role in endometrial carcinogenesis.

There are three common non-synonymous polymorphisms in the MGMT gene, Leu84Phe, Ile143Val and Lys178Arg, and the latter two are in linkage disequilibrium (12–14). The Leu84Phe polymorphism is 15 amino acids upstream of the LXXLL motif. The Ile143Val polymorphism is two amino acids away from the 145 cysteine alkyl-residue. The two polymorphisms were reported to be associated with decreased capacity of repairing smoking-related DNA damage (15). To date, no studies have been published that examine the associations of these two polymorphisms in the MGMT gene with endometrial cancer risk. We assessed these associations and their interactions with cigarette smoking and estrogen-related risk factors in a nested case–control study within the Nurses’ Health Study.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Study population
The Nurses’ Health Study was established in 1976, when 121 700 female registered nurses between the ages of 30 and 55 completed a self-administered questionnaire on their medical histories and baseline health-related exposures. Updated information has been obtained by questionnaires every 2 years, including data on reproductive variables, oral contraceptive, postmenopausal hormone use, cigarette smoking and BMI. Between 1989 and 1990, blood samples were collected from 32 826 of the cohort members. Subsequent follow-up has been >98% for this subcohort. In 2000–2002, cheek cell samples were collected from 32 883 NHS women who had not provided a blood sample in 1989–1990 (16).

In this study, we included both incident and prevalent endometrial cancer cases from the blood and cheek cell subcohorts of the NHS. Eligible incident cases in the blood cohort consisted of women with pathologically confirmed invasive endometrial cancer diagnosed any time after blood collection up to June 1, 2000, with no previously diagnosed cancer except for non-melanoma skin cancer. Prevalent cases in the blood cohort were defined as having pathologically confirmed invasive endometrial cancer diagnosed between 1976 and the date of blood collection, with no previously diagnosed cancer except non-melanoma 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 non-melanoma 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 HRT use at blood draw (current versus not current) as well as time of day, month and fasting status at blood draw. We had 141 incident cases with 386 matched controls, and 118 prevalent cases with 354 matched controls in the blood cohort. In the cheek cell cohort, all cases had pathologically confirmed invasive endometrial cancer diagnosed between 1976 and the date of cheek cell collection, with no previously diagnosed cancer except non-melanoma skin cancer. Two controls per case were randomly selected from participants who gave a cheek cell sample, had not had a hysterectomy and were free of diagnosed cancer (except non-melanoma skin cancer) up to and including the interval in which the case was diagnosed. The matching criteria were year of birth, menopausal status, HRT use (current versus not current) and month and year of cheek cell collection. We have 197 cases and 394 controls in the cheek cell cohort. In total, the case–control study consists of 456 invasive cases and 1134 matched controls. The protocol was approved by the Committee on Human Subjects, Brigham and Women's Hospital.

Exposure data
Information regarding endometrial cancer risk factors was obtained from the 1976 baseline questionnaire, subsequent biennial questionnaires and a questionnaire completed at the time of blood sampling. Cigarette smoking, menopausal status and postmenopausal hormone use, including the dose and duration of current use of conjugated estrogen or estrogen plus progestin, were asked in the prospective questionnaires and updated until the date of diagnosis for cases and the equivalent date for matched controls. First-degree family history of endometrial and colorectal cancer was assessed retrospectively from the 1996 follow-up questionnaire.

Genotyping assays
Genotyping was done by the 5' nuclease assay (TaqMan), using the ABI PRISM 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA), in 384-well format. TaqMan primers and probes were designed using the Primer Express Oligo Design software version 2.0 (ABI PRISM). Laboratory personnel were blinded to case–control status, and 5% blinded quality-control samples were inserted to validate genotyping procedures; concordance for the blinded samples was 100%. Primers, probes and conditions for genotyping assays are available on request.

Statistical analysis
We used a {chi}2-test to assess whether the genotypes were in Hardy–Weinberg equilibrium. Conditional logistic regression was employed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the risk of endometrial cancer among all women. Unconditional logistic regression was used in stratified analyses and interaction analyses adjusted for matching factors. To test the interactions between the risk factors and the genotypes, we modeled genotypes as dichotomous variables and risk factors as ordinal variables to assess the significance of a single multiplicative interaction term. This interaction test evaluated whether the trend for the risk factor was statistically significantly different according to the genotype. Tests for trend were conducted by using median values for categories of risk factors as a continuous variable. All P-values were two-sided.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Because prevalent blood cases had to be alive in 1989 to donate blood and prevalent cheek cell cases had to be alive in 2000 to donate cheek cell samples, we first compared the distribution of the genotypes between incident blood, prevalent blood and prevalent cheek cell cases to assess whether the alleles influence endometrial cancer survival. The genotype frequencies were not significantly different between prevalent and incident cases (84Phe carriers: 20.1% versus 22.2%, {chi}2, df = 1, P = 0.61; 143Val carriers: 24.9% versus 20.6%, {chi}2, df = 1, P = 0.32). Because we did not observe evidence of ‘survivor bias’, incident and prevalent cases were combined and analyzed together. Basic characteristics of the cases and controls are presented in Table I.


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  		Table I Selected characteristics of the case–control study within the Nurses' Health Study

 
The genotype distributions of the two polymorphisms were in accordance with Hardy–Weinberg equilibrium among controls. We observed that, compared with the 84Leu/Leu genotype, the Phe carriers had a multivariate OR of 0.72 (95%CI, 0.53–0.96) for endometrial cancer risk (Table II). When stratified by menopausal status, the inverse association was observed among postmenopausal women (OR, 0.72; 95%CI, 0.52–0.99), but not among premenopausal women (OR, 1.35; 95%CI, 0.71–2.56). Overall, there was no association between the Ile143Val polymorphism and endometrial cancer risk or by menopausal status.


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  		Table II Polymorphisms in MGMT and endometrial cancer risk

 
There was no significant interaction between the Leu84Phe polymorphism and either pack-years of smoking (P, interaction, 0.30) or smoking status at diagnosis (never, past and current) (P, interaction, 0.65) on endometrial cancer risk. However, we did observe a significant interaction between the Ile143Val polymorphism and pack-years of smoking on endometrial cancer risk (Table III); the trend for pack-years of smoking with endometrial cancer risk was statistically significantly different according to the genotype (P, interaction, 0.04). The inverse association of pack-years of smoking with endometrial cancer risk was observed among the 143Val carriers (P, trend, 0.01); the decreased risk was confined among those who had >30 pack-years of smoking. There was no apparent inverse association among the 143Val non-carriers (P, trend, 0.70). In the cross-classified analyses, compared with the common reference group of women who had the Ile/Ile genotype and never smoked, the 143Val carriers who had >30 pack-years of smoking had a significantly decreased risk of endometrial cancer (OR, 0.41; 95%CI, 0.19–0.86). The carriage of the 143Val allele was significantly associated with a decreased risk of endometrial cancer only in the stratum of 30 or more pack-years of smoking. We did not observe an interaction between the polymorphism and smoking status at diagnosis (P, interaction, 0.29).


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  		Table III Interaction between the MGMT polymorphisms and cigarette smoking at diagnosis on endometrial cancer risk

 
Because MGMT also inhibits ER-mediated cell proliferation, we examined the interactions between the two polymorphisms and BMI (<25, 25–30 and ≥30) and postmenopausal hormone use (current, past and never use) among postmenopausal women. We did not observe significant interactions between the Leu84Phe and BMI (P, interaction, 0.63) or postmenopausal hormone use (P, interaction, 0.15). No significant interactions were found for the Ile143Val polymorphism (P, interaction with BMI, 0.67; P, interaction with postmenopausal hormone use, 0.44).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
In this study, two or three controls per case were selected in the blood subcohort; two controls per case were selected in cheek cell subcohort. The effort of selecting multiple controls per case is intended to increase statistical power. The controls are healthy women without prior history of cancer except for non-melanoma skin cancer among the blood and cheek cell subcohorts. The criterion, absence of hysterectomy, is to make sure that only the participants who have an intact uterus are eligible as controls. There are very few asymptomatic endometrial cancer cases in our study. If there were some asymptomatic endometrial cancer cases, this would only dilute the point estimate and bias towards the null. Therefore, our results would be even stronger. Our incident and prevalent cases are similar because of their early presentation of disease, the high 5 year survival rates and the small number of case deaths before bio-sample collection. Because we did not observe survivor bias, incident and prevalent cases were combined and analyzed together.

We observed a significant inverse association between the Leu84Phe polymorphism and endometrial cancer risk. Overall, we did not observe an association between the Ile143Val polymorphism and endometrial cancer risk. Three-dimensional structural modeling of MGMT revealed that the 84Leu, 143Ile and 145cysteine alkyl residues pack in a hydrophobic region with the LXXLL motif (17), suggesting that the two polymorphisms may affect both the MGMT functions, inhibiting ER-mediated cell proliferation and DNA repair. Adipose tissue is the primary source of endogenous estrogen in postmenopausal women, and body weight has been shown to be correlated with endogenous estrogen levels in postmenopausal women (18–20). However, we did not observe any significant interactions between either of the polymorphisms and BMI or postmenopausal hormone use.

Cigarette smoking has been consistently associated with a 20–40% decrease in endometrial cancer risk (1,2). One leading hypothesis is that this inverse association is due to the anti-estrogenic effects of smoking (1–3). The inverse association between cigarette smoking and endometrial cancer risk has been shown to be similar among past and current smokers (1,4–6). Pack-years of smoking before the age of 30 is also inversely associated with endometrial cancer risk (1). These data suggest that cigarette smoking may have a protective effect on the early stage of endometrial carcinogenesis. Cigarette smoking can cause alkylation damage and it is well known that a natural biological response to the accumulation of alkylation damage is to trigger apoptosis, a form of programmed cell death that results in efficient elimination of unwanted cells. In the uterus, mounting evidence suggests that apoptosis is necessary in maintaining cellular homeostasis by eliminating senescent cells from endometrium in the late secretary and menstrual phase of the menstrual cycle in premenopausal women (21–23).

Several inconsistent reports have been published on the DNA repair function of the Leu84Phe and Ile143Val polymorphisms in the MGMT gene. Both polymorphisms have been shown to be associated with suboptimal repair of genetic damage, as measured by the in vitro nicotine-derived nitrosamino ketone (NNK) induced chromosome aberration assays, in the lymphocytes from 114 healthy controls (15). However, Inoue et al. (24) reported that Escherichia coli cells carrying 84Phe and wild-type sequences had similar enzymatic and physicochemical properties. The two polymorphisms did not show effects on DNA repair capacity by in vitro mutagenesis in E.coli (25). The effect of the two polymorphisms on the MGMT's capacity to inhibit ER-mediated cell proliferation is unknown. Inconsistent associations have been reported between the two polymorphisms and the risk of bladder (26), colon (17) and breast cancer (27,28). Without a rigorous functional assessment, the results from the association studies for the two polymorphisms should be interpreted with caution.

In this study, we did observe a significant interaction between the Ile143Val polymorphism and long-term smoking as measured by pack-years of smoking. The inverse association of pack-years of smoking and endometrial cancer risk was stronger among the 143Val carriers. Among women who carried the 143Val allele and had >30 pack-years of smoking, we observed a 60% decrease in endometrial cancer risk. The reduction in risk conferred by the carriage of the 143Val allele was limited to those with >30 pack-years of smoking.

On the basis of these findings, it is intriguing to speculate that the inverse association between cigarette smoking and endometrial cancer risk may be mediated through an additional mechanism, possibly apoptosis. Apoptosis can be triggered by DNA damage, and there could be accumulation of DNA damage resulting from decreased DNA repair capacity or/and high exposure to DNA-damaging agents. One well-established example is sun exposure-induced apoptosis in the skin tissue (29). It has been shown that the activity of apoptosis in the endometrium is high, which is not surprising since it undergoes cyclical growth, differentiation and shedding (21). This constant ‘renewal’ of the endometrium may help remove the cells damaged by cigarette smoking, which can decrease endometrial cancer risk. Given the reduced repair activity of the 143Val allele, one plausible explanation for the observed interaction is that the endometrial tissues with compromised DNA repair capacity, when challenged with a high dose of exposure, may accumulate smoking-induced damage, thus further inducing apoptosis and decreasing the risk of endometrial cancer. We observed a similar interaction pattern in skin carcinogenesis; the polymorphisms that were associated with decreased DNA repair capacity were associated with decreased risk of skin cancer, and the inverse association was more apparent among those with high levels of sun exposure (30,31).

In summary, we observed a significant inverse association between the Leu84Phe polymorphism and endometrial cancer risk. Moreover, we observed a significant interaction between the Ile143Val polymorphism and pack-years of smoking on endometrial cancer risk. These findings are novel and require confirmation. Additional studies, both epidemiological and biological, are warranted to follow up this working hypothesis on endometrial carcinogenesis.


   Acknowledgments
 
We thank Dr Hardeep Ranu and Craig Labadie for their laboratory assistance, and Dr Monica McGrath and Carolyn Guo for their programming support. We are also indebted to the participants in the Nurses’ Health Study for their dedication and commitment. This work is supported by NIH grants CA082838 (I.D.) and CA049449 (S.E.H.), and American Cancer Society Research Scholar Grant RSG-0006104-CCE (I.D.).

Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received March 18, 2006; revised June 1, 2006; accepted June 3, 2006.


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