Skip Navigation


Carcinogenesis Advance Access originally published online on November 4, 2007
Carcinogenesis 2008 29(1):100-105; doi:10.1093/carcin/bgm247
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/1/100    most recent
bgm247v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Huang, W.-Y.
Right arrow Articles by Hsing, A. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Huang, W.-Y.
Right arrow Articles by Hsing, A. W.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Published by Oxford University Press 2007.

Selected base excision repair gene polymorphisms and susceptibility to biliary tract cancer and biliary stones: a population-based case–control study in China

Wen-Yi Huang1,*, Yu-Tang Gao2, Asif Rashid3, Lori C. Sakoda4, Jie Deng2, Ming-Chang Shen5, Bin-Sheng Wang6, Tian-Quan Han7, Bai-He Zhang8, Bingshu E. Chen1, Philip S. Rosenberg1, Stephen J. Chanock1,9 and Ann W. Hsing1

1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA
2 Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China
3 Department of Pathology, MD Anderson Cancer Center, Houston, TX77030, USA
4 Department of Epidemiology, University of Washington, Seattle, WA 98198, USA
5 Shanghai Tumor Hospital
6 Zhongshan Hospital, Fudan University, Shanghai, China
7 Ruijin Hospital, Shanghai Second Medical University, Shanghai, China
8 Oriental Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
9 Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892, USA

* To whom correspondence should be addressed. Tel: +1 301 435 4710; Fax: +1 301 402 1819; Email: huangw{at}mail.nih.gov


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 
Base excision repair (BER) corrects DNA damage caused by oxidative stress and chronic inflammation, putative risk factors for cancer. To understand the relationship between genetic variation in BER genes and risk of biliary tract cancer and biliary stones, we examined non-synonymous polymorphisms in three key BER genes—x-ray repair cross-complementing group 1 (XRCC1) (R194W, rs1799782; R280H, rs25489 and R399Q, rs25487), apurinic/apyrimidinic endonuclease (APEX1) (D148E, rs3136820) and 8-oxoguanine DNA glycosylase (OGG1) (S326C, rs1052133), in a population-based study of 411 biliary tract cancer cases (237 gallbladder, 127 bile duct and 47 ampulla of Vater), 891 biliary (gallbladder or bile duct) stone cases and 786 population controls conducted in Shanghai, China. Compared with subjects carrying the XRCC1 194RR genotype, those with the WW genotype had a 1.9-fold risk of bile duct cancer [odds ratio (OR) = 1.9, 95% confidence interval (CI) = 1.1–3.5, Ptrend = 0.03], and compared with subjects carrying the XRCC1 280RR genotype, those with the XRCC1 280H allele had a 50% reduced risk of bile duct cancer (OR = 0.5, 95% CI = 0.3–0.9, Ptrend = 0.05). The effect of the R280H polymorphism persisted (Ptrend = 0.03), when all three XRCC1 polymorphisms were jointly considered in the model, a finding supported by the haplotype results (covariate-adjusted global permutation P = 0.03). We also found an inverse association between the APEX1 148E allele and gallbladder stones (Ptrend = 0.03), but no association for the OGG1 polymorphism. This study suggests that genetic variants in XRCC1 and APEX1 may alter susceptibility to biliary tract cancer and stones. Further studies are required to confirm the reported associations.

Abbreviations: APEX1, apurinic/apyrimidinic endonuclease; BER, base excision repair; BMI, body mass index; CI, confidence interval; OGG1, 8-oxoguanine DNA glycosylase; OR, odds ratio; SNP, single-nucleotide polymorphism; XRCC1, x-ray repair cross-complementing group 1


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Funding
 References
 
Cancers of the biliary tract, encompassing the gallbladder, extrahepatic bile ducts and ampulla of Vater are rare but often fatal malignancies (1). In Shanghai, China, they have been the most rapidly rising malignancies over the last three decades (2). Apart from established risk factors for biliary tract cancer, including age, gender and a history of biliary stones (gallbladder or bile duct stones), environmental and lifestyle factors such as chronic inflammation due to infections, obesity, westernized diet and hormonal factors are suspected to play a role (2).

Several putative risk factors for biliary tract cancer can cause increased generation of reactive oxygen species and oxidative damage. Obesity and certain chronic inflammatory conditions involving the biliary tract (e.g. biliary stones, primary sclerosing cholangitis and Clonorchis sinensis infections) have been associated with increased serum concentrations of cytokines and nitric oxide (3,4) and these mediators promote oxidative DNA damage and inhibit repair of DNA damage in cholangiocytes (5) and cholangiocarcinoma cells (6). Evidence exists that dietary constituents including glucose and other macronutrients can cause oxidative stress and inflammatory changes (3). Exposure to estrogen and its metabolites has been shown in vitro to induce DNA single-strand breaks and oxidized DNA bases (7). Moreover, the clustering of biliary tract cancer within families suggests a critical role for genetics in biliary carcinogenesis (8).

Base excision repair (BER), a highly conserved mechanism, because of its importance in the repair of oxidative and hydrolytic damage is postulated to be important for biliary tract cancer (9,10). BER involves three steps: (i) removal of the damaged base by a DNA glycosylase, such as 8-oxoguanine DNA glycosylase (OGG1), generating an apurinic/apyrimidinic site; (ii) cleavage of the phosphodiester bond by apurinic/apyrimidinic endonuclease (APEX1) and (iii) gap filling by DNA polymerase β and nick sealing by the DNA ligase III and x-ray repair cross-complementing group 1 (XRCC1) complex, resulting in replacement of a single nucleotide, a process called short-patch BER, or alternatively replacement of nucleotides, the long-patch repair, which involves flap endonuclease 1, proliferating cell nuclear antigen and DNA ligase I (9,10).

We studied risk of biliary tract cancer and biliary stones associated with common genetic variation in key BER genes in a population-based case–control study in China. In particular, this study analyzed non-synonymous single-nucleotide polymorphisms (SNPs) in three genes, XRCC1: R194W (Ex6–22C>T, rs1799782), R280H (Ex9+16G>A, rs25489) and R399Q (Ex10–4A>G, rs25487), APEX1: D148E (Ex5+5T>G, rs3136820) and OGG1: S326C (Ex6–315C>G, rs1052133).


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Funding
 References
 
Study population
Details about the design of this population-based, case–control study of biliary tract cancer and biliary stones in Shanghai, China, have been presented elsewhere (11–13). Briefly, 627 newly diagnosed, histopathologically confirmed biliary tract cancer patients were enrolled between June 1997 and May 2001 through a rapid reporting system established across 42 collaborating hospitals in urban Shanghai. The study was effective in capturing >95% of all eligible biliary tract cancer patients in the study area and time period. Also, 1037 biliary stone cases with no history of cancer were enrolled and frequency matched to the index cancer cases by age (5-year intervals), gender and hospital to permit assessment of unique and shared risk factors for biliary tract cancer versus stones. Of the eligible population controls randomly selected from all permanent residents listed in Shanghai Resident Registry who were without a history of cancer and frequency-matched to cancer cases by age (5-year intervals) and gender, 959 (82%) agreed to participate. A cancer diagnosis was confirmed by expert review of histology slides and/or clinical data from computed tomography scan, magnetic resonance imaging, abdominal ultrasound and endoscopic retrograde cholangiopancreatography. Biliary stone cases were confirmed by abdominal ultrasound, endoscopic retrograde cholangiopancreatography films and pathology review for those who underwent a cholecystectomy. In addition, a history of biliary stones was assessed for cancer cases and population controls. For cancer cases, we used data from clinical diagnostic workup (abdominal ultrasound, computed tomography scan, endoscopic retrograde cholangiopancreatography and magnetic resonance imaging), medical records and personal interview, where individuals reporting a prior cholecystectomy or gallstones were classified as having had biliary stones. For population controls, a history of biliary stones was determined by interview data (for 15% of the controls) and by abdominal ultrasound data, performed on 85% of the controls who agreed to the ultrasound screening for detection of silent biliary stones. All participants provided written informed consent. The study protocol was approved by the Institutional Review Boards of the US National Cancer Institute and Shanghai Cancer Institute.

Data and specimen collection
An in-person interview was conducted for all participants to collect information potentially related to biliary tract cancer and stones, including demographics, consumption of cigarettes, alcohol, tea and other dietary factors, anthropometry, physical activity, reproductive history and hormone use (for females), personal history of selected medical conditions, family history of cancer and occupation. To ensure that data were consistently collected with high quality, all interviews were tape recorded and reviewed, and for 5% of the study population, a second interview was administered within three months, showing >90% concordance between the interviews for responses to key questions. Over 80% of the participants donated an overnight fasting blood sample and half of the participants were randomly selected to provide a 24-h urine sample for the study.

Blood processing and genotyping
Buffy coat samples were processed within 4 h of collection at a laboratory in Shanghai Cancer Institute, stored at –70°C and shipped to the USA on dry ice for DNA extraction by the phenol–chloroform method. For the present study, DNA samples were available for 411 (66%) biliary tract cancer cases (237 gallbladder, 127 bile duct and 47 ampulla of Vater), 891 (86%) biliary stone cases (670 gallbladder and 221 bile duct) and 786 (82%) population controls. Of those with DNA samples, genotyping was successfully carried out for >99% of the samples for all five studied SNPs at the National Cancer Institute Core Genotyping Facility (Gaithersburg, MD). All genotype assays were validated and optimized (http://snp500cancer.nci.nih.gov) (14). Eighty blinded duplicates from four individuals were interspersed with study samples and showed >98% concordance for all five SNPs. Laboratory personnel were blinded to the case–control status of the samples.

Statistical analysis
For each tested SNP, departure from fitness for Hardy–Weinberg proportion in controls was evaluated by comparing the observed to the expected genotype frequencies using a chi-square test. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between genotype of each polymorphism and anatomic subsite of the biliary tract cancer and biliary stones, adjusting for age and gender. Further adjustment for biliary stone status, a predominant risk factor for biliary tract cancer and for consumption of potential sources of oxidative stress and antioxidants, including smoking, alcohol, fruits, vegetables and preserved food, led to no material change of results for all associations and are not presented herein. Subjects with cholecystectomy (n = 49) were excluded from the population controls when making comparison with gallbladder cancer cases and subjects with biliary stones (n = 78) were eliminated from the population controls in comparison with biliary stone cases, whereas bile duct and ampullary cancer cases were compared with all population controls. A trend test for each genotype was performed according to the number of copies of the variant allele (0, 1 or 2). Statistical significance of the multiplicative interaction between DNA repair genotype and covariate [e.g. body mass index (BMI), biliary stones or other factors assessed] was assessed by comparing nested models with and without the cross-product terms, using a likelihood ratio statistic. The R-based program HaploStats (http://mayoresearch.mayo.edu/mayo/research/schaid_lab/software.cfm) was used to assess disease risks associated with haplotypes defined by the three SNPs in XRCC1, taking into account the extent of haplotype uncertainty based on an expectation–maximization algorithm (15,16), in which a global score test was used to evaluate overall differences in haplotype frequencies between cases and controls adjusted for covariates and an implemented generalized linear model was used to assess the effect of individual haplotypes on cancer risk. To account for multiple SNPs studied for XRCC1, a summary P value of the overall association between the XRCC1 genetic variation and each outcome of interest was derived using Simes global test controlling for family-wise error rates; this ensures that the chance that any XRCC1 SNP is erroneously declared to be associated with the disease, if in fact no XRCC1 SNP is truly associated, will be less than or equal to a prespecified value (17). We further conducted an omnibus test to combine results from both the SNP and haplotype analyses and provided a single adjusted P value for the XRCC1 gene (18).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Funding
 References
 
Table I shows selected characteristics of the study subjects. Compared with the population controls, more women than men were diagnosed with gallbladder cancer (P = 0.0008) and gallbladder stones (P = 0.0007), whereas more men than women were diagnosed with bile duct cancer (P < 0.0001). Gallbladder stone (P < 0.0001) and bile duct stone (P = 0.04) cases were younger than the population controls. Gallbladder stones and bile duct stones were more common among the cancer cases (85, 68 and 60% of gallbladder, bile duct and ampulla of Vater cancer cases, respectively) than the population controls (25%). Gallbladder cancer (P = 0.0002), gallbladder stone (P < 0.0001) and bile duct stone (P = 0.002) cases had a greater BMI than the population controls. Bile duct cancer (P = 0.002) and ampullary cancer (P = 0.08) cases were more likely, whereas gallbladder stone cases (P = 0.002) were less likely, to report ever smoking at least one cigarette per day for ≥6 months than the population controls. Regarding alcohol consumption, compared with the population controls, a greater percentage of bile duct cancer patients (P = 0.003), whereas a smaller percentage of gallbladder cancer (P = 0.07) and gallbladder stone (P = 0.0006) patients, reported regular use.


View this table:
[in this window]
[in a new window]

  		Table I. Percent distribution of selected characteristics of cases and controls

 
Table II shows the risk of biliary tract cancer and biliary stones associated with polymorphisms of the three genes. Among the population controls, no deviation from fitness for Hardy–Weinberg proportion was observed (P > 0.3) for all SNPs. Compared with subjects carrying the XRCC1 194RR genotype, those with the 194WW genotype had a 1.9-fold risk of bile duct cancer (OR = 1.9, 95% CI = 1.1–3.5, Ptrend = 0.03). In contrast, subjects carrying the XRCC1 280H allele had a 50% reduced risk of bile duct cancer (OR = 0.5, 95% CI = 0.3–0.9, Ptrend = 0.05) compared with those carrying the XRCC1 280RR genotype.


View this table:
[in this window]
[in a new window]

  		Table II. ORs and 95% CIs for biliary tract cancer and biliary stones in relation to selected DNA repair polymorphisms

 
Table III shows risk of biliary tract cancer and biliary stones associated with the XRCC1 haplotypes. The three XRCC1 SNPs were in linkage disequilibrium (D' = 1.0 for all pairwise comparisons and r2 ranging from 0.04 to 0.2), but the effect of the R280H polymorphism persisted (Ptrend = 0.03) after all three XRCC1 SNPs were included in the same logistic regression model. Based on the three SNPs in XRCC1 (R194W, R280H and R399Q), we inferred four common haplotypes, specifically R-R-R, W-R-R, R-R-Q and R-H-R with corresponding frequencies of 31, 31, 27 and 10% among the control subjects. For bile duct cancer, XRCC1 haplotype frequencies differed between cases and controls (covariate-adjusted global permutation P = 0.03). It appeared that the haplotype effect was driven by the 280H variant (OR = 0.5, 95% CI = 0.3–1.0 comparing R-H-R with R-R-R).


View this table:
[in this window]
[in a new window]

  		Table III. ORs and 95% CIs for biliary tract cancer and biliary stones in relation to common haplotypes of the three non-synonymous polymorphisms of XRCC1

 
Risk of bile duct cancer associated with the XRCC1 SNPs was modified by biliary stone status (Table IV, top panel; Pinteraction between 0.01 and <0.0001). The excess bile duct cancer risk associated with the 194W variant (OR = 2.3, 95% CI = 1.1–4.8, Pinteraction < 0.0001) and the reduced bile duct cancer risk associated with the 280H variant (OR = 0.3, 95% CI = 0.1–1.1, Pinteraction = 0.01) were more pronounced among subjects with no biliary stones. A significantly reduced risk of bile duct cancer was found only for carriers of the 399Q variant who had biliary stones (Pinteraction = 0.0001). Also, the reduced bile duct cancer risk associated with the 280H allele was found only among subjects with a BMI < 23 kg/m2 (Table IV, bottom panel; P = 0.03) and a reduced bile duct cancer risk was found only for carriers of the 399Q allele whose BMI was ≥23 kg/m2 (P = 0.04).


View this table:
[in this window]
[in a new window]

  		Table IV. ORs and 95% CIs for bile duct cancer and gallbladder stones in relation to selected DNA repair genotypes by biliary stone status and BMI

 
In addition, a significantly increased risk of ampullary cancer, albeit with a wide CI, was found for carriers of the XRCC1 280HH genotype (Table II; OR = 7.6, 95% CI = 1.4–40.8, Ptrend = 0.02) and a significantly reduced risk of gallbladder stones was found for carriers of the APEX1 148EE genotype (OR = 0.7, 95% CI = 0.5–0.9, Ptrend = 0.03) compared with those homozygous for the most common allele. The increased risk of gallbladder stones associated with the APEX1 148E allele was most pronounced for subjects with a BMI ≥ 23 kg/m2 (Table IV, bottom panel; Pinteraction = 0.002). No effect was seen for the other SNPs and biliary disease subsites.

Additional adjustment for biliary stone status did not alter the results when cancer cases were compared with the population controls. Adjustment for consumption of smoking, alcohol, preserved food, fruits and vegetables or stratification by these factors did not show any apparent confounding or effect modification effects. Statistical adjustment for the multiple SNPs studied for XRCC1 also did not affect the interpretation of the results: the adjusted P value by Simes global test for the overall association between the three XRCC1 SNPs and bile duct cancer was 0.075. The P value by the omnibus test that considered both the SNP and haplotype results for the association between the XRCC1 SNPs and bile duct cancer was 0.06.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Funding
 References
 
BER proteins excise and replace damaged DNA bases, mainly those arising from endogenously generated oxidative and hydrolytic damage (19). We hypothesize that BER may be particularly important for the biliary tract cancer because oxidized DNA bases and single-strand breaks have been associated with chronic inflammation (3), obesity (4), certain nutrients rich in westernized diet (3) and hormonal factors (7), putative risk factors for biliary tract cancer. In this population-based study in China, we found a modest association between the XRCC1 gene variants (R194W, R280H and R399Q) and bile duct cancer, and the association persisted after statistical adjustment for the multiple SNPs studied. Specifically, the XRCC1 194W variant was associated with an increased risk and the 280H variant was related to a reduced risk of bile duct cancer. Bile duct cancer risk was most clearly associated with the XRCC1 R280H polymorphism and the association was most pronounced among subjects with no biliary stones and those with a BMI < 23 kg/m2. We also found a significantly reduced risk of gallbladder stones for carriers of the APEX1 148E variant, particularly for those with a BMI ≥ 23 kg/m2. These results suggest that genetic variants in XRCC1 and APEX1 affect risk of biliary tract cancer and stones and warrant further study.

In this first molecular epidemiologic study of DNA repair genes and biliary tract cancer, we focus on common non-synonymous SNPs in three key BER genes. The SNPs under study have been evaluated in previous epidemiologic studies of other cancer sites. In the meta-analyses combining all cancer sites, the XRCC1 194W variant was associated with a 11% reduced risk of cancer (20), the XRCC1 280H variant was associated with a 19% increased risk of cancer (20), whereas XRCC1 399Q (20), APEX1 148E (9) and OGG1 326C (9) were unrelated to cancer risk. Findings across the different cancer sites, however, were contradictory, thus a direct comparison of the results was not attempted. It appeared that XRCC1 280H, XRCC1 194W and OGG1 326C were most common in East Asia as in our study population, thereby increasing our likelihood of detecting an association with these variants.

The XRCC1 protein acts as a scaffold protein coordinating the action of the short-patch BER (9), has been demonstrated to be essential for efficient single-strand break repair and genomic stability (21,22), and its gene resides in an evolutionarily conserved region. All three studied polymorphisms are located in the interacting binding region of XRCC1 (23,24), and both R194W and R399Q encode a non-conservative amino acid change. The APEX1 protein initiates the BER process by cleaving the DNA backbone (25) and acts as co-activator for ubiquitous and tissue-specific transcription factors, important for intracellular control of reactive oxygen species (26). The APEX1 D148E polymorphism is located within the endonuclease domain of the protein (27), but the residue is not well conserved across species and the polymorphism encodes a conservative amino acid change. Although the XRCC1 194W (28), 280H (29) and 399Q (30–34) variants and the APEX1 148E variant (31) have been associated with increased DNA damage and altered DNA repair capacity and susceptibility to mutagens, conflicting reports also exist for 194W (29,31,32,34,35), 399Q (24,36,37) and 148E (38). Replication in future epidemiologic studies are required to confirm the associations we reported.

Due to small numbers, we were limited in the statistical power to examine gene–environment interactions. For example, although aspirin use was associated with a reduced risk of gallbladder, bile duct and ampullary cancers in our study (12), due to the low prevalence of aspirin use in Shanghai (5.7%), we were unable to evaluate interactions between aspirin use and BER gene variants. However, we found statistically significant interactions between BMI and XRCC1 variants for the risk of bile duct cancer and between BMI and the APEX1 variant for the risk of gallbladder stones. Although these associations are biologically plausible (3–6), caution is needed in interpreting the subgroup findings.

History of biliary stones is an established risk factor for biliary tract cancer, consistent with findings in our study (11). Biliary stone status was not a confounder for any of the associations found in our study between biliary tract cancer and BER SNPs, whereas certain associations were modified by biliary stone status. For example, the significant reduction of bile duct cancer risk associated with the XRCC1 280H variant and the significant increase of bile duct cancer risk associated with the XRCC1 194W variant were observed only among subjects with no biliary stones, suggesting that the XRCC1 genetic variation may contribute to bile duct cancer risk through mechanisms independent of biliary stones.

Selection and survival biases in this population-based study were minimal due to the nearly complete case ascertainment and high response rates. Misclassification of outcome was also minimal since both cancer and stone cases had rigorous clinical and pathology review. Of the population controls, 85% underwent ultrasound detection of biliary stones, and silent stones were detected for only 6% (of those who underwent the procedures, i.e. 85% of the controls), thus potential misclassification due to silent biliary stones among the 15% of the controls for whom we relied on self-reported data is expected to be small (less than seven individuals). High-quality genotyping, as evidenced by the high reproducibility rate among blinded quality control samples, minimized the potential for genotype misclassification. In addition, the inclusion of two case groups, the biliary tract cancer and biliary stone groups, allows us to assess whether risks associated with various exposures are similar between these two closely related disease outcomes. Because few studies of biliary tract cancer are available to replicate our findings, we focused on functionally relevant candidate SNPs to reduce the likelihood of mere chance findings, and we implemented statistical adjustment for multiple SNPs studied.

Gene coverage in our study is limited since SNP selection was not based on complete sequencing data of the study population. Consistent with the associations with chronic hepatitis history (11) and a common inflammation gene variant PTGS2 Ex10+837C (13) that we found only for bile duct cancer, not gallbladder or ampullary cancers, it is plausible that the association of the XRCC1 variants found herein only for bile duct cancer is etiologic relevant. However, given the small number of bile duct and ampullary cancers available for study, we cannot rule out the possibility of chance findings. Also despite being the largest population-based study of biliary tract cancer to date, we were precluded from rigorous assessment of possible gene–environment interactions. Generalizability of our results is limited due to the fairly homogeneous Chinese population in Shanghai; however, the concern of population stratification should be minimal.

We found that genetic variants in XRCC1 and APEX1 affect the risk of bile duct cancer and gallbladder stones, suggesting that genetic variation in DNA repair genes may alter susceptibility to biliary tract cancer and stones. Further studies are needed to confirm these findings and to characterize the specific genetic variants responsible for the development of biliary tract cancer and the interrelationship with obesity and other risk factors.


   Funding
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
References
 
Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics.


   Acknowledgments
 
We thank Jiarong Cheng, Lu Sun, Kai Wu, Enju Liu and the staff at the Shanghai Cancer Institute for data collection, specimen collection and processing; collaborating hospitals and surgeons for data collection; local pathologists for pathology review; Shelley Niwa and Hope Webb-Cohen of Westat for data preparation and management; Janis Koci of the Scientific Applications International Corporation for management of the biological samples and Meredith Yeager and Robert Welch of the Core Genotyping Facility for their input on genotyping.

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Funding
 References
 

  1. Hsing AW, et al. Biliary tract cancer. In: Cancer Epidemiology and Prevention—Schottenfeld D, ed. (2006) 3rd. New York: Oxford University Press. 787–800.
  2. Hsing AW, et al. Rising incidence of biliary tract cancers in Shanghai, China. Int. J. Cancer (1998) 75:368–370.[CrossRef][Web of Science][Medline]
  3. Dandona P, et al. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. (2004) 25:4–7.[CrossRef][Web of Science][Medline]
  4. Olszanecka-Glinianowicz M, et al. Serum concentrations of nitric oxide, tumor necrosis factor (TNF)-alpha and TNF soluble receptors in women with overweight and obesity. Metabolism (2004) 53:1268–1273.[CrossRef][Web of Science][Medline]
  5. Jaiswal M, et al. Nitric oxide-mediated inhibition of DNA repair potentiates oxidative DNA damage in cholangiocytes. Gastroenterology (2001) 120:190–199.[CrossRef][Web of Science][Medline]
  6. Jaiswal M, et al. Inflammatory cytokines induce DNA damage and inhibit DNA repair in cholangiocarcinoma cells by a nitric oxide-dependent mechanism. Cancer Res. (2000) 60:184–190.[Abstract/Free Full Text]
  7. Rajapakse N, et al. Detection of DNA strand breaks and oxidized DNA bases at the single-cell level resulting from exposure to estradiol and hydroxylated metabolites. Environ. Mol. Mutagen. (2005) 45:397–404.[CrossRef][Web of Science][Medline]
  8. Lichtenstein P, et al. Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J. Med. (2000) 343:78–85.[Abstract/Free Full Text]
  9. Hung RJ, et al. Genetic polymorphisms in the base excision repair pathway and cancer risk: a HuGE review. Am. J. Epidemiol. (2005) 162:925–942.[Abstract/Free Full Text]
  10. Ide H, et al. Human DNA glycosylases involved in the repair of oxidatively damaged DNA. Biol. Pharm. Bull. (2004) 27:480–485.[CrossRef][Web of Science][Medline]
  11. Hsing AW, et al. Biliary tract cancer and stones in relation to chronic liver conditions: a population-based study in Shanghai, China. Int. J. Cancer (2007) 120:1981–1985.[CrossRef][Web of Science][Medline]
  12. Liu E, et al. Aspirin use and risk of biliary tract cancer: a population-based study in Shanghai, China. Cancer Epidemiol. Biomarkers Prev. (2005) 14:1315–1318.[Abstract/Free Full Text]
  13. Sakoda LC, et al. Prostaglandin-endoperoxide synthase 2 (PTGS2) gene polymorphisms and risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China. Carcinogenesis (2006) 27:1251–1256.[Abstract/Free Full Text]
  14. Packer BR, et al. SNP500Cancer: a public resource for sequence validation and assay development for genetic variation in candidate genes. Nucleic Acids Res. (2004) 32:D528–D532.[Abstract/Free Full Text]
  15. Lake SL, et al. Estimation and tests of haplotype-environment interaction when linkage phase is ambiguous. Hum. Hered. (2003) 55:56–65.[CrossRef][Web of Science][Medline]
  16. Schaid DJ, et al. Score tests for association between traits and haplotypes when linkage phase is ambiguous. Am. J. Hum. Genet. (2002) 70:425–434.[CrossRef][Web of Science][Medline]
  17. Simes RJ. An improved Bonferroni procedure for multiple tests of significance. Biometrika (1986) 73:751–754.[Abstract/Free Full Text]
  18. Rosenberg PS, et al. Multiple hypothesis testing strategies for genetic case-control association studies. Stat. Med. (2006) 25:3134–3149.[CrossRef][Web of Science][Medline]
  19. Wood RD, et al. Human DNA repair genes. Science (2001) 291:1284–1289.[Abstract/Free Full Text]
  20. Hu Z, et al. XRCC1 polymorphisms and cancer risk: a meta-analysis of 38 case-control studies. Cancer Epidemiol. Biomarkers Prev. (2005) 14:1810–1818.[Abstract/Free Full Text]
  21. Whitehouse CJ, et al. XRCC1 stimulates human polynucleotide kinase activity at damaged DNA termini and accelerates DNA single-strand break repair. Cell (2001) 104:107–117.[CrossRef][Web of Science][Medline]
  22. Brem R, et al. XRCC1 is required for DNA single-strand break repair in human cells. Nucleic Acids Res. (2005) 33:2512–2520.[Abstract/Free Full Text]
  23. Fan J, et al. XRCC1 co-localizes and physically interacts with PCNA. Nucleic Acids Res. (2004) 32:2193–2201.[Abstract/Free Full Text]
  24. Taylor RM, et al. Central role for the XRCC1 BRCT I domain in mammalian DNA single-strand break repair. Mol. Cell Biol. (2002) 22:2556–2563.[Abstract/Free Full Text]
  25. McCullough AK, et al. Initiation of base excision repair: glycosylase mechanisms and structures. Annu. Rev. Biochem. (1999) 68:255–285.[CrossRef][Web of Science][Medline]
  26. Tell G, et al. The intracellular localization of APE1/Ref-1: more than a passive phenomenon? Antioxid. Redox Signal. (2005) 7:367–384.[CrossRef][Web of Science][Medline]
  27. Walker LJ, et al. Identification of residues in the human DNA repair enzyme HAP1 (Ref-1) that are essential for redox regulation of Jun DNA binding. Mol. Cell Biol. (1993) 13:5370–5376.[Abstract/Free Full Text]
  28. Leng S, et al. The association of XRCC1 haplotypes and chromosomal damage levels in peripheral blood lymphocyte among coke-oven workers. Cancer Epidemiol. Biomarkers Prev. (2005) 14:1295–1301.[Abstract/Free Full Text]
  29. Takanami T. The Arg280His polymorphism in X-ray repair cross-complementing gene 1 impairs DNA repair ability. Mutat. Res. (2005) 582:135–145.[Web of Science][Medline]
  30. Duell EJ, et al. Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells. Carcinogenesis (2000) 21:965–971.[Abstract/Free Full Text]
  31. Hu JJ, et al. Amino acid substitution variants of APE1 and XRCC1 genes associated with ionizing radiation sensitivity. Carcinogenesis (2001) 22:917–922.[Abstract/Free Full Text]
  32. Lunn RM, et al. XRCC1 polymorphisms: effects on aflatoxin B1-DNA adducts and glycophorin A variant frequency. Cancer Res. (1999) 59:2557–2561.[Abstract/Free Full Text]
  33. Matullo G, et al. XRCC1, XRCC3, XPD gene polymorphisms, smoking and (32)P-DNA adducts in a sample of healthy subjects. Carcinogenesis (2001) 22:1437–1445.[Abstract/Free Full Text]
  34. Wang Y, et al. From genotype to phenotype: correlating XRCC1 polymorphisms with mutagen sensitivity. DNA Repair (Amst.) (2003) 2:901–908.[CrossRef][Medline]
  35. Abdel-Rahman SZ, et al. The 399Gln polymorphism in the DNA repair gene XRCC1 modulates the genotoxic response induced in human lymphocytes by the tobacco-specific nitrosamine NNK. Cancer Lett. (2000) 159:63–71.[CrossRef][Web of Science][Medline]
  36. Palli D, et al. DNA adduct levels and DNA repair polymorphisms in traffic-exposed workers and a general population sample. Int. J. Cancer (2001) 94:121–127.[CrossRef][Web of Science][Medline]
  37. Tuimala J, et al. Genetic polymorphisms of DNA repair and xenobiotic-metabolizing enzymes: role in mutagen sensitivity. Carcinogenesis (2002) 23:1003–1008.[Abstract/Free Full Text]
  38. Hadi MZ, et al. Functional characterization of Ape1 variants identified in the human population. Nucleic Acids Res. (2000) 28:3871–3879.[Abstract/Free Full Text]
Received September 13, 2007; revised October 24, 2007; accepted October 30, 2007.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 MutagenesisHome page
D. Gu, M. Wang, M. Wang, Z. Zhang, and J. Chen
The DNA repair gene APE1 T1349G polymorphism and cancer risk: a meta-analysis of 27 case-control studies
Mutagenesis, November 1, 2009; 24(6): 507 - 512.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Epidemiol. Biomarkers Prev.Home page
M. Zhang, W.-Y. Huang, G. Andreotti, Y.-T. Gao, A. Rashid, J. Chen, L. C. Sakoda, M.-C. Shen, B.-S. Wang, S. Chanock, et al.
Variants of DNA Repair Genes and the Risk of Biliary Tract Cancers and Stones: A Population-Based Study in China
Cancer Epidemiol. Biomarkers Prev., August 1, 2008; 17(8): 2123 - 2127.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
A. W. Hsing, L. C. Sakoda, A. Rashid, G. Andreotti, J. Chen, B.-S. Wang, M.-C. Shen, B. E. Chen, P. S. Rosenberg, M. Zhang, et al.
Variants in Inflammation Genes and the Risk of Biliary Tract Cancers and Stones: A Population-Based Study in China
Cancer Res., August 1, 2008; 68(15): 6442 - 6452.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
29/1/100    most recent
bgm247v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Huang, W.-Y.
Right arrow Articles by Hsing, A. W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Huang, W.-Y.
Right arrow Articles by Hsing, A. W.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?