Polymorphisms in base excision repair genes are associated with endometrial cancer risk among postmenopausal Japanese women.

ORIGINAL STUDY

Polymorphisms in Base Excision Repair Genes Are Associated With Endometrial Cancer Risk Among Postmenopausal Japanese Women Satoyo Hosono, MD, PhD,* Keitaro Matsuo, MD, PhD,*¶ Hidemi Ito, MD, PhD,*Þ Isao Oze, MD, PhD,* Kaoru Hirose, PhD,þ Miki Watanabe, MSc,* Toru Nakanishi, MD, PhD,§ Kazuo Tajima, MD, PhD,|| and Hideo Tanaka, MD, PhD*Þ Objectives: Polymorphisms in base excision repair (BER) genes are associated with risk for several types of cancers but have not been studied with respect to endometrial cancer among Japanese women. Therefore, we conducted a case-control study to explore the association between polymorphisms in BER genes and the risk for endometrial cancer. Methods/Materials: This study included a total of 91 postmenopausal subjects with endometrial cancer and 261 controls without cancer who visited the Aichi Cancer Center between 2001 and 2005. We focused on single nucleotide polymorphisms within coding regions of 5 BER genes (OGG1, MUTYH, XRCC1, APEX1, and PARP1). To assess lifestyle in the etiology of endometrial cancer, we used a self-administered questionnaire. Associations were evaluated using multivariate unconditional logistic regression models. We also assessed whether there were intergenic associations or an interaction with obesity. Results: We observed a significant association between endometrial cancer risk and XRCC1 rs1799782 (C 9 T, Arg194Trp) and XRCC1 rs25487 (G 9 A, Arg399Gln). We uncovered a significant association between obesity (body mass index, Q25) and rs25487. The XRCC1 polymorphisms were in complete linkage disequilibrium, and the XRCC1 haplotype TG associated significantly with endometrial cancer risk. The interaction between the CA haplotype and body mass index was marginally significant, whereas interaction between haplotype in XRCC1 and rs1136410 (PARP1) was not significant. Conclusions: We found a significant association between endometrial cancer risk and XRCC1 polymorphisms and haplotype TG in postmenopausal Japanese women. Key Words: Case-control study, Base excision repair gene polymorphisms, Endometrial cancer, Japanese women, XRCC1 Received May 31, 2013, and in revised form July 29, 2013. Accepted for publication August 4, 2013. (Int J Gynecol Cancer 2013;23: 1561Y1568)

*Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute; †Department of Epidemiology, Nagoya University Graduate School of Medicine; ‡Department of Planning and Information, Aichi Prefectural Institute of Public Health; §Department of Gynecologic Oncology, Aichi Cancer Center Hospital; ||Department of Public Health and Occupational Medicine, Mie University Graduate School of Medicine; and ¶Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences. Address correspondence and reprint requests to Keitaro Matsuo, MD, PhD, Division of Epidemiology and Copyright * 2013 by IGCS and ESGO ISSN: 1048-891X DOI: 10.1097/IGC.0b013e3182a80a7e International Journal of Gynecological Cancer

Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. E-mail: [email protected]. Supported by JSPS KAKENHI grant number 23791866, National Cancer Center Research and Development Fund; a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare of Japan; and a Grant-in-Aid for Scientific Research on Priority Areas of Cancer (no. 17015018) and Innovative Areas (no. 221S0001) from the Japanese Ministry of Education, Culture, Sports, Science and Technology. The authors declare no conflicts of interest.

& Volume 23, Number 9, November 2013

Copyright © 2013 by IGCS and ESGO. Unauthorized reproduction of this article is prohibited.

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International Journal of Gynecological Cancer

Hosono et al

cancer is one of the most frequent gynecoE ndometrial logical malignancies in the world. Although the incidence 1

in Asian nations, including Japan, is lower than that in industrialized Western nations,2 the most recent epidemiological data show that there has been a marked increase in the age-standardized incidence rate in Japan from 3.9 in 1990, 5.1 in 2000, to 8.1 in 2007.3 Major risk factors of endometrial cancer are as follows: obesity, nulliparity, late menopause, exogenous unopposed estrogen, tamoxifen, diabetes, hypertension, high dietary fat consumption, radiation therapy, and hereditary nonpolyposis colorectal cancer.4 Much of the risk for endometrioid carcinoma can be attributed to exposure to unopposed estrogen resulting primarily from unopposed postmenopausal estrogen therapy and obesity4,5; however, a large proportion of endometrial cancer cases cannot be completely explained by these factors. Recent technological advances in genotyping enable researchers to uncover the association between single nucleotide polymorphisms (SNPs) and susceptibility to diseases, including cancer. An important aspect of the application of these techniques has been the discovery of genetic variation in DNA repair genes, which results in defects in DNA repair and is related to the risk for certain cancers.6,7 Evidence exists to indicate that polymorphisms in DNA repair genes associate with endometrial cancer.8Y11 In contrast, the association of polymorphisms in DNA repair genes with endometrial cancer in the Japanese population remains to be investigated in detail. Here, we conducted a hospital-based case-control study to examine the association between various polymorphisms in base excision repair (BER) DNA pathway genes (OGG1, MUTYH, XRCC1, APEX1, and PARP1) among Japanese postmenopausal women with and without endometrial cancer. We also determined whether these associations were influenced by obesity and gene-gene interactions.

MATERIALS AND METHODS Subjects The subjects included 91 postmenopausal patients newly and histologically diagnosed with endometrial carcinoma between January 2001 and November 2005 at the Aichi Cancer Center Hospital in Japan. The distribution of histological subtypes among cases was 59 with endometrioid adenocarcinoma (64.8%), 26 with other types of carcinoma (28.6%), and 6 with tumors that we were unable to identify (6.6%). Controls (n = 261) were randomly selected from 11,814 women who were diagnosed as cancer-free at the Aichi Cancer Center Hospital between January 2001 and November 2005 and who were also postmenopausal. All subjects were recruited within the framework of the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), as described elsewhere.12Y14 In brief, we asked all first-visit outpatients aged 20 to 79 years to provide information on lifestyle factors using a self-administered questionnaire and a sample of blood. The patients were also asked about their lifestyle when healthy or before the current symptoms developed. A trained interviewer checked responses. Our previous study showed that the lifestyle patterns of first-visit outpatients were comparable with a randomly selected sample of the population of Nagoya City.15

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All participants provided written informed consent, and the Institutional Ethical Committee of Aichi Cancer Center approved this study.

Exposure Data Smoking and drinking habits were categorized as never, former, and current. Former smokers and drinkers (designated ‘‘ever-smokers’’ and ‘‘ever-drinkers’’) were included with current smokers and drinkers for analysis. Body mass index (BMI) at enrollment was calculated from self-reported height and weight as BMI (kg/m2) = weight (kg)/height (m2). In the present study, regular exercise was defined as at least 1 session each month.

Genotyping of DNA Repair Genes DNA was extracted from the buffy coat fraction of blood samples using a Blood Mini Kit (Qiagen KK, Tokyo, Japan) and analyzed using the polymerase chain reaction (PCR) TaqMan method with 7500 Real-Time PCR System (Applied Biosystems).16 The probes used were designed to detect rs1052133 (OGG1), rs36053993 (MUTYH), rs1799782 (XRCC1), rs25487 (XRCC1), rs1130409 (APEX1), and rs1136410 (PARP1). Genotyping was conducted in duplicate in cases that deviated from the Hardy-Weinberg equilibrium (HWE). Linkage disequilibrium (LD) was evaluated by means of LD coefficients (D’).

Statistical Analysis To assess the strength of associations between the polymorphisms and risk for endometrial cancer, odds ratios (ORs) with 95% confidence intervals (CIs) per allele were estimated using unconditional logistic models adjusted for potential confounders. Potential confounders considered in the multivariate analyses were age, smoking (never or ever), consumption of alcohol (never or ever), current BMI (G25 or Q25 kg/m2), regular exercise (yes or no), age at menarche (e12, 13Y14, or Q15 years), age at menopause (e39, 40Y54, or Q55 years), parity (0, 1Y2, or Q 3), history of diabetes (yes or no), history of hypertension (yes or no), use of contraceptives (yes or no), and hormone replacement therapy (yes or no). Differences in categorized demographic variables between the cases and the controls were determined using the W2 test. Age, BMI, age at menarche, age at menopause, and parity between the cases and the controls were compared using the Mann-Whitney U test. To explore the interaction between current BMI and each locus, we conducted further analysis stratified by BMI (G25 or Q25 kg/m2) based on our previous study.12 Furthermore, we evaluated the interactions between XRCC1 haplotype and current BMI and rs1136410 (PARP1). These were assessed by logistic regression models including score for current BMI (G25, 0; Q25, 1), score for each locus (major homozygote, 0; heterozygote, 1; minor homozygote, 2), score for XRCC1 haplotype (haplotype CG, 0; CA, 1; TG, 2), and their interaction terms. Genotypes were designated as scores. We applied a retrospective profile-likelihood method in logistic regression to estimate haplotype effects using the ‘‘haplologit’’ command.17P values less than 0.05 were considered statistically significant. All analyses were conducted using STATA * 2013 IGCS and ESGO




TABLE 1. (Continued)

TABLE 1. Characteristics of subjects Cases No. 91 Histology endometrioid 59 (64.8) other 26 (28.6) unknown 6 (6.6) Age Median (range) 59 (35Y79) G50 4 (4.4) 50Y59 45 (49.5) 60Y69 31 (34.1) Q70 11 (12.1) Smoking status Ever 17 (18.7) Never 73 (80.2) Unknown 1 (1.1) Alcohol consumption Ever 25 (27.5) Never 65 (71.4) Unknown 1 (1.1) BMI Median (range) 23.4 (16.7Y40.9) G25 kg/m2 63 (69.2) Q25 kg/m2 26 (28.6) Unknown 2 (2.2) Regular exercise No 32 (35.2) Yes 59 (64.8) Age at menarche Median (range) 14 (11Y18) e12 9 (20.9) 13Y14 23 (50.6) Q15 15 (24.2) Unknown 1 (4.4) Age at menopause Median (range) 52 (28Y59) e39 2 (2.2) 40Y55 80 (87.9) 955 8 (8.8) Unknown 1 (1.1) Parity Median (range) 2 (0Y4) 0 12 (13.2) 1Y2 65 (71.4) Q3 13 (14.3)

XRCC1 and Endometrial Cancer Risk

Controls

P

261

62 (35Y79) 5 (1.9) 91 (34.9) 89 (34.1) 76 (29.1)

0.003 0.004

26 (10.0) 235 (90.0) 0 (0)

0.026

77 (29.5) 184 (70.5) 0 (0)

0.756

Cases Unknown Diabetes No Yes Hypertension No Yes Oral contraception No Yes Unknown Hormone replacement therapy No Yes Unknown

P

Controls

1 (1.1)

1 (0.4)

83 (91.2) 8 (8.8)

242 (92.7) 19 (7.3)

0.641

71 (78.0) 20 (22.0)

212 (81.2) 49 (18.8)

0.507

85 (93.4) 5 (5.5) 1 (1.1)

249 (95.4) 11 (4.2) 1 (0.4)

0.604

80 (87.9) 10 (11.0) 1 (1.1)

246 (94.3) 14 (5.4) 1 (0.4)

0.064

Values are number (percentage) unless otherwise indicated.

version 10.1 (Stata Corp, College Station, TX). Linkage disequilibrium estimates were calculated using STATA.

22.6 (16.7Y33.3) 0.008 209 (80.1) 0.051 50 (19.2) 2 (0.8) 70 (26.8) 191 (73.2)

0.131

14 (11Y20) 43 (16.5) 119 (45.6) 90 (34.5) 9 (3.5)

0.182 0.186

50 (14Y60) 12 (4.6) 238 (91.2) 10 (3.8) 1 (0.4)

0.002 0.116

2 (0Y4) 32 (12.3) 156 (59.8) 72 (27.6)

0.016 0.039

RESULTS Baseline characteristics of the 91 endometrial cancer patients and the 261 controls are shown in Table 1. The median age for the cases was lower than that for the controls (P = 0.003). In contrast, current BMI was significantly higher than in the controls (P = 0.008). Smoking was more common among the cases. Alcohol consumption did not differ significantly between the groups. With respect to the subjects’ reproductive history, low parity was more prevalent (P = 0.016) and age at menopause was higher among the cases than the controls (P = 0.002). A history of hormone replacement therapy was more common in the cases. There were no significant differences between the groups in their histories of diabetes, hypertension, and contraceptive use. The distributions of genotypes of 6 DNA repair gene polymorphisms and their impacts on endometrial cancer risk are shown in Table 2. Genotype distributions of each locus among the controls were in accordance with the HWE, without taking into account the data for OGG1 and MUTYH. In the per-allele model, the significant associations between endometrial cancer risk and XRCC1 are as follows: rs1799782 (C 9 T, Arg194Trp) (CT: OR, 1.79; 95% CI, 1.01Y3.18; TT: OR, 2.87; 95% CI, 1.25Y6.64; trend P = 0.004) and XRCC1 rs25487 (G 9 A, Arg399Gln) (GA: OR, 0.64; 95% CI, 0.37Y1.11; AA: OR, 0.14; 95% CI, 0.02Y1.12; trend P = 0.008). Table 3 shows the interaction between current BMI (e25 or 925) and each locus. A significant interaction between BMI and XRCC1 rs25487 was observed (interaction P = 0.048).

* 2013 IGCS and ESGO


1563

1564

dbSNP rs Number 3p26.2

1p34.1

19q13.2

19q13.2

14q11.2

1q41Yq42

9773773

45569815

48749414

48747566

19994994

224621925

Chromosomal Position Chromosome

Val762Ala

Asp248Glu

Arg399Gln

Arg194Trp

Gly382Asp

Ser326Cys

Residue Change

0.455

0.318

0.279

0.278

No data

0.523

0.385

0.366

0.269

0.305

0

0.490

0.734

0.415

0.819

0.722

V

0.022

29/100 47/121 15/40

35/108 43/115 13/38

57/137 33/106 1/18

30/125 46/113 15/23

91/261

30/77 40/112 21/72

Hap-Map MAF in HWE P in Case/ JPT Controls Controls Control, n

1 (Reference) 1.39 (0.80Y2.40) 1.59 (0.76Y3.36) 0.167

1 (Reference) 1.19 (0.70Y2.01) 1.15 (0.55Y2.44) 0.591

1 (Reference) 0.72 (0.44Y1.20) 0.13 (0.02Y1.03) 0.025

1 (Reference) 1.71 (1.00Y2.90) 2.47 (1.13Y5.38) 0.011

NA NA

1 (Reference) 0.83 (0.47Y1.46) 0.73 (0.38Y1.39) 0.330

Age-Adjusted OR (95% CI)

1 (Reference) 1.42 (0.78Y2.58) 1.74 (0.78Y3.89) 0.162

1 (Reference) 1.10 (0.63Y1.93) 0.92 (0.41Y2.07) 0.940

1 (Reference) 0.64 (0.37Y1.11) 0.14 (0.02Y1.12) 0.008

1 (Reference) 1.79 (1.01Y3.18) 2.87 (1.25Y6.64) 0.004

NA NA

1 (Reference) 0.88 (0.47Y1.62) 0.77 (0.38Y1.55) 0.508

Multivariate OR (95% CI)*



*Multivariate models adjusted for age, current BMI, smoking, alcohol consumption, regular exercise, age at menarche, age at menopause, parity, diabetes, oral contraception, and hormone replacement therapy. JPT, Japanese in Tokyo, Japan; NA indicates Not assessed; MAF, minor allele frequency.

Rs1052133 CC CG GG P for trend MUTYH_1 Rs36053993 GG P for trend XRCC1 Rs1799782 CC CT TT P for trend XRCC1 Rs25487 GG GA AA P for trend APEX1 Rs1130409 TT TG GG P for trend PARP1 Rs1136410 TT TC CC P for trend

OGG1

Gene

TABLE 2. Impact of BER pathway gene polymorphisms on endometrial cancer risk

Hosono et al





Table 4 shows the impacts of XRCC1 haplotype rs1799782 and rs25487 on the risk for endometrial cancer, which were in complete LD (D¶ = 1.00), and specifically in relation to BMI (G25 or 925) and PARP1 rs1136410 polymorphism (TT or TC/ CC). The XRCC1 TG haplotype was significantly associated with the increased risk for endometrial cancer (OR, 1.49; 95% CI, 1.02Y2.18). In contrast, only a marginally significant interaction between the XRCC1 CA haplotype and current BMI was observed (interaction P = 0.087). The postmenopausal women with XRCC1 TG haplotype and PARP1 rs1136410 C allele had a significantly increased risk (OR, 1.63; 95% CI, 1.01Y2.62).


However, a significant interaction between XRCC1 haplotype and PARP1 rs1136410 polymorphism was not detected.

DISCUSSION Here, among the selected polymorphisms in genes involved in the BER pathway, our analyses revealed a significant association between polymorphisms in XRCC1 and endometrial cancer risk in postmenopausal Japanese women. The XRCC1 polymorphisms rs1799782 and rs25487 in XRCC1 were in complete LD, and the TG haplotype was significantly associated with endometrial cancer. Only a

TABLE 3. Impact of individual BER pathway gene polymorphisms on endometrial cancer risk according to BMI

Gene

dbSNP rs Number

Rs1052133 CC CG GG P for trend MUTYH_1 Rs36053993 GG P for trend XRCC1 Rs1799782 CC CT TT P for trend XRCC1 Rs25487 GG GA AA P for trend APEX1 Rs1130409 TT TG GG P for trend PARP1 Rs1136410 TT TC CC P for trend

BMI Q 25

BMI G 25

Overall

Case/ Case/ Case/ Control, Multivariate Control, Multivariate Control, Multivariate OR Interaction n OR (95% CI)* n OR (95% CI)* n (95% CI)* P

OGG1

30/77 1 (Reference) 3/62 40/112 0.88 (0.47Y1.62) 28/89 21/72 0.77 (0.38Y1.55) 12/58 0.508

1 (Reference) 0.99 (0.47Y2.07) 0.55 (0.23Y1.34) 0.211

7/14 11/22 8/14

1 (Reference) 0.69 (0.15Y3.08) 2.26 (0.44Y11.63) 0.342

NA NA

26/50

NA NA

30/125 1 (Reference) 21/101 1 (Reference) 46/113 1.79 (1.01Y3.18) 33/91 1.94 (0.97Y3.86) 15/23 2.87 (1.25Y6.64) 9/17 3.13 (1.08Y9.08) 0.004 0.016

9/22 11/22 6/6

1 (Reference) 1.45 (0.36Y5.73) 3.82 (0.53Y27.39) 0.209

57/137 1 (Reference) 35/114 1 (Reference) 33/106 0.64 (0.37Y1.11) 27/80 0.79 (0.41Y1.51) 1/18 0.14 (0.02Y1.12) 1/15 0.20 (0.02Y1.67) 0.008 0.133

20/22 6/25 0/3

1 (Reference) 0.10 (0.02Y0.54) V 0.002

35/108 1 (Reference) 26/91 43/115 1.10 (0.63Y1.93) 28/89 13/38 0.92 (0.41Y2.07) 9/29 0.940

1 (Reference) 1.26 (0.65Y2.46) 1.10 (0.41Y2.95) 0.668

9/16 13/25 4/9

1 (Reference) 1.03 (0.28Y3.76) 0.75 (0.11Y4.97) 0.825

0.413 0.740

29/100 1 (Reference) 16/79 47/121 1.42 (0.78Y2.58) 37/99 15/40 1.74 (0.78Y3.89) 10/31 0.162

1 (Reference) 1.86 (0.89Y3.91) 1.71 (0.61Y4.81) 0.186

12/21 9/20 5/9

1 (Reference) 0.93 (0.24Y3.61) 1.10 (0.16Y7.48) 0.963

0.516 0.801

91/261

NA NA

63/209

0.543 0.352

NA

0.696 0.943

0.048

*Multivariate models adjusted for age, BMI, smoking, alcohol consumption, regular exercise, age at menarche, age at menopause, parity, diabetes, oral contraception, and hormone replacement therapy. NA indicates Not assessed.



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*P G 0.05. †Multivariate models adjusted for age, BMI, smoking, alcohol consumption, regular exercise, age at menarche, age at menopause, parity, diabetes, oral contraception, and hormone replacement therapy.

1 (Reference) 0.83 (0.48Y1.43) 1.63 (1.01Y2.62)* V 1 (Reference) 0.66 (0.29Y1.49) 1.30 (0.68Y2.49) V 0.087 0.773 V 1 (Reference) 1 (Reference) 1 (Reference) 0.76 (0.31Y1.21) 1.05 (0.62Y1.77) 0.29 (0.11Y0.87)* 1.49 (1.02Y2.18)* 1.62 (1.03Y2.57)* 1.03 (0.49Y2.17) V V V 0.433 0.262 0.304 0 rs1799782 rs25487 C G C A T G T A

Interaction P Multivariate OR (95% CI)† Interaction Multivariate P OR (95% CI)† Multivariate OR (95% CI)† Multivariate OR (95% CI)† XRCC1 Haplotype

Haplotype Frequency in Controls

Multivariate OR (95% CI)†

PARP1VTC and CC PARP1VTT BMI Q 25 BMI G 25 Overall

TABLE 4. Haplotype analysis of XRCC1 for endometrial cancer risk: interaction with BMI and PARP1 rs1136410

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0.304 0.457 V


Hosono et al


marginally significant interaction between the CA haplotype and current BMI was observed, whereas an interaction between XRCC1 haplotype and PARP1 rs1136410 was not significant. This is the first study, to our knowledge, to explore the associations of genetic variation in BER genes and endometrial cancer in a Japanese population. Evidence indicates that estrogens and their metabolites damage DNA by the formation of bulky DNA adducts,18 which are repaired by the nucleotide excision repair pathway. Therefore, earlier studies examined the association between the genetic variations in nucleotide excision repair pathway and endometrial cancer.8 The BER pathway functions to repair small lesions in DNA, such as oxidized or reduced bases and fragmented or nonbulky adducts.6 There is extensive evidence indicating that the accumulation of oxidative damage to DNA leads to genomic instability, resulting in cancer.19 However, there are relatively few biological and epidemiological studies that focus on the role of BER in endometrial carcinogenesis. For example, Samulak et al9 concluded that the XRCC1 Arg399Gln polymorphism may be associated with the incidence of sporadic endometrial cancer in Polish women, and Cincin et al10 reported that the XRCC1 Gln399Gln and HOGG1 Ser326Cys genotypes increase the risk for type I endometrial cancer in Turkish women. In another study of Polish women, Sobczuk et al11 found that gene-gene interaction between the ERCC2 751Gln and XRCC1 194Trp variants increased the risk for endometrial cancer. To investigate the association between endometrial cancer and polymorphisms in the BER pathway (OGG1, MUTYH, XRCC1, APEX1, and PARP1) in Japanese women, we selected 6 coding SNPs. Our findings suggest that XRCC1 polymorphisms play an important role in endometrial cancer among postmenopausal women. XRCC1 encodes a scaffolding protein that plays a pivotal role in the BER pathway by forming a complex with PARP, DNA ligase 3, and DNA polymerase A.20 Functional studies on XRCC1 polymorphisms are limited; however, XRCC1 399Gln (rs25487, Arg399Gln) in human cells might be associated with higher sensitivity of DNA damage after exposure to various mutagens, and XRCC1 194Trp (rs1799782, Trp194Arg) seems to have lower mutagen sensitivity in vitro.7 Although these common nonsynonymous SNPs in XRCC1, including rs25487,21,22 rs25489,21 and rs1799782,21,22 have been studied extensively in various cancers, the evidence is inconsistent regarding whether these are etiologically associated. Meta-analyses of these XRCC1 polymorphisms and cancer risk demonstrate that an A allele carrier of rs25487 is likely to have an increased risk for bladder,6 breast,6,23 lung,23 and colorectal cancer.24 In contrast, individuals carrying the T allele of rs1799782 are at decreased risk for skin7 and upper digestive tract cancer 23 as well as all types of cancers.24,25 Because these findings are inconsistent with those reported here, further investigation of larger populations and functional studies are warranted. Alternatively, this apparent discrepancy could be explained by our selection of Japanese subjects. The interaction between rs25487 in XRCC1 and current BMI was significant in our study. Obesity is an established * 2013 IGCS and ESGO




risk factor of endometrial cancer, and it affects the synthesis and the bioavailability of endogenous sex steroid hormones, mainly estrogens.5 It is known that the levels of markers of oxidative stress correlated significantly with BMI and that excess estrogen exposure leads to the elevated generation of reactive oxygen species.26Y28 Moreover, Dai et al29 demonstrated a significant interaction of oxidative stress markers and BMI on breast cancer risk among Chinese women, although endometrial cancer was not addressed in this study. In contrast, a gene-gene interaction between XRCC1 haplotype and PARP1 polymorphism was not significant in our present study. However, on the basis of their mechanisms of action19,20 and studies of genetic associations,30 an interaction between XRCC1 and PARP1 is biologically plausible.20 Polymorphisms in BER genes and their interactions might represent a target for further biological and epidemiological research on the carcinogenesis of endometrial cancer. Potential limitations of our study warrant consideration. First, we selected 6 coding SNPs in 5 BER genes on the basis of previous studies. Work is now in progress in our laboratory to search for other BER gene polymorphisms that might be relevant to the etiology of endometrial carcinogenesis. Second, our study design represents a hospital-based casecontrol study. However, we previously examined the external validity of the HERPACC study.15 Further, the HERPACC system is less prone to intrinsic information bias because we collected data before the diagnosis of the subjects. Finally, the sample size of our study was relatively small, and our study was conducted within central Japan. Therefore the HWE of OGG1 rs1052133 could be disturbed. We plan to conduct studies of larger populations in Japan. Consequently, we could consider the difference between histological subtype. In our preliminary stratified analysis by histological subtype, we observed the same trend (data not shown) despite the small sample size. A larger sample is required to clarify the difference between histological subtype. In conclusion, our research reveals a significant association between XRCC1 rs1799782 and rs25487 and endometrial cancer risk in postmenopausal Japanese women. XRCC1 rs1799782 and rs25487 were in complete LD. The TG haplotype was significantly associated with endometrial cancer. In contrast, a marginally significant interaction between the CA haplotype and current BMI was observed, but we did not detect a significant interaction between XRCC1 and PARP1 polymorphisms. Our study adds to the evidence supporting a role for polymorphisms in DNA repair genes in the etiology of endometrial cancer.

ACKNOWLEDGEMENTS The authors thank the administrative staff at the Division of Epidemiology and Prevention at Aichi Cancer Center Research Institute for their support of this study.

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3. Matsuda T, Marugame T, Kamo K, et al. Cancer incidence and incidence rates in Japan in 2006: based on data from 15 population-based cancer registries in the monitoring of cancer incidence in Japan (MCIJ) project. Jpn J Clin Oncol. 2012;42: 139Y147. 4. Fader AN, Arriba LN, Frasure HE, et al. Endometrial cancer and obesity: epidemiology, biomarkers, prevention and survivorship. Gynecol Oncol. 2009;114:121Y127. 5. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev. 2002;11:1531Y1543. 6. Goode EL, Ulrich CM, Potter JD. Polymorphisms in DNA repair genes and associations with cancer risk. Cancer Epidemiol Biomarkers Prev. 2002;11:1513Y1530. 7. Hung RJ, Hall J, Brennan P, et al. Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review. Am J Epidemiol. 2005;162:925Y942. 8. Weiss JM, Weiss NS, Ulrich CM, et al. Interindividual variation in nucleotide excision repair genes and risk of endometrial cancer. Cancer Epidemiol Biomarkers Prev. 2005;14: 2524Y2530. 9. Samulak D, Romanowicz-Makowska H, Smolarz B, et al. Association between Arg399Gln polymorphism of x-ray repair cross-complementing 1 (XRCC1) gene and sporadic endometrial cancer in the Polish population. Eur J Gynaecol Oncol. 2011;32:491Y495. 10. Cincin ZB, Iyibozkurt AC, Kuran SB, et al. DNA repair gene variants in endometrial carcinoma. Med Oncol. 2012;29: 2949Y2954. 11. Sobczuk A, Poplawski T, Blasiak J. Polymorphisms of DNA repair genes in endometrial cancer. Pathol Oncol Res. 2012;18:1015Y1020. 12. Hosono S, Matsuo K, Kajiyama H, et al. Reduced risk of endometrial cancer from alcohol drinking in Japanese. Cancer Sci. 2008;99:1195Y1201. 13. Tajima K, Hirose K, Inoue M, et al. A model of practical cancer prevention for out-patients visiting a hospital: the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). Asian Pac J Cancer Prev. 2000;1:35Y47. 14. Hamajima N, Matsuo K, Saito T, et al. Gene-environment interactions and polymorphism studies of cancer risk in the Hospital-based Epidemiologic Research Program at Aichi Cancer Center II (HERPACC-II). Asian Pac J Cancer Prev. 2001;2:99Y107. 15. Inoue M, Tajima K, Hirose K, et al. Epidemiological features of first-visit outpatients in Japan: comparison with general population and variation by sex, age, and season. J Clin Epidemiol. 1997;50:69Y77. 16. Livak KJ. Allelic discrimination using fluorogenic probes and the 5¶ nuclease assay. Genet Anal. 1999;14:143Y149. 17. Marchenko YV, Caroll RJ, Lin DY, et al. Semiparametric analysis of case-control genetic data in the presence of environmental factors. Stata J. 2008;8:305Y333. 18. Zhu BT, Conney AH. Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis. 1998;19:1Y27. 19. Maynard S, Schurman SH, Harboe C, et al. Base excision repair of oxidative DNA damage and association with cancer and aging. Carcinogenesis. 2009;30:2Y10. 20. Robertson AB, Klungland A, RognesT, et al. DNA repair in mammalian cells: base excision repair: the long and short of it. Cell Mol Life Sci. 2009;66:981Y993.



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TP53 and MDM2 polymorphisms and the risk of endometrial cancer in postmenopausal women.

Nucleotide excision repair pathway gene polymorphisms are linked to breast cancer risk in a Chinese population.

A risk-scoring model for the prediction of endometrial cancer among symptomatic postmenopausal women with endometrial thickness > 4 mm.

Polymorphisms in alternative splicing associated genes are associated with lung cancer risk in a Chinese population.

Detection of endometrial cancer in postmenopausal women.

Serum Estrogens and Estrogen Metabolites and Endometrial Cancer Risk among Postmenopausal Women.

Base excision DNA repair and cancer.

Polymorphism of the DNA base excision repair genes in keratoconus.

A polymorphism in the base excision repair gene PARP2 is associated with differential prognosis by chemotherapy among postmenopausal breast cancer patients.

How are base excision DNA repair pathways deployed in vivo?

DNA glycosylases involved in base excision repair may be associated with cancer risk in BRCA1 and BRCA2 mutation carriers.

Vitamin D receptor gene polymorphisms and breast cancer risk among postmenopausal Egyptian women.

Polymorphisms in VDR gene in Tunisian postmenopausal women are associated with osteopenia phenotype.

Plasma amino acid profiles are associated with biomarkers of breast cancer risk in premenopausal Japanese women.

Variants of Base Excision Repair Genes MUTYH , PARP1 and XRCC1 in Alzheimer's Disease Risk.

Polymorphisms of estrogen metabolism-related genes ESR1, UGT2B17, and UGT1A1 are not associated with osteoporosis in surgically menopausal Japanese women.

Single-nucleotide polymorphisms of microRNA processing machinery genes are associated with risk for gastric cancer.

DNA modifications repaired by base excision repair are epigenetic.

MUTYH the base excision repair gene family member associated with colorectal cancer polyposis.

Genetic Polymorphisms of TGFB1, TGFBR1, SNAI1 and TWIST1 Are Associated with Endometrial Cancer Susceptibility in Chinese Han Women.

Genetic polymorphisms in estrogen-related genes and the risk of breast cancer among Han Chinese women.

Association of DNA base excision repair genes (OGG1, APE1 and XRCC1) polymorphisms with outcome to platinum-based chemotherapy in advanced nonsmall-cell lung cancer patients.

Risk factors associated with sexual dysfunction in Brazilian postmenopausal women.

Sugar-sweetened beverage intake and the risk of type I and type II endometrial cancer among postmenopausal women.