Selected DNA repair polymorphisms and gastric cancer in Poland

Wen-Yi Huang 1, *, Wong-Ho Chow 1, Nat Rothman 1, Jolanta Lissowska 2, Victor Llaca 3, Meredith Yeager 3, Witold Zatonski 2 and Richard B. Hayes 1

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 Division of Cancer Epidemiology and Prevention, Cancer Center and M.Sklodowska-Curie Institute of Oncology, 02-781 Warsaw, Poland and 3 Core Genotyping Facility, Advanced Technology Center, National Cancer Institute-Frederick, Gaithersburg, MD 20892, USA

* To whom correspondence should be addressed: Division of Cancer Epidemiology and Genetics, National Cancer Institute, EPS 8113, MSC 7240, Bethesda, MD 20892, USA. Tel: +301 435 4710; Fax: +301 402 1819; Email: huangw{at}mail.nih.gov


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Impaired DNA repair capacity may adversely affect cancer risk, particularly in subjects exposed to DNA damaging carcinogens, as found in tobacco smoke, or among subjects deficient for protective factors, as found in fruits and vegetables. We studied tobacco use, fruit and vegetable intake, and common non-synonymous single nucleotide polymorphisms in four DNA repair genes in relation to gastric cancer risk, in a population-based, case–control study of 281 incident gastric cancer cases and 390 controls, in Warsaw, Poland. Multivariate logistic regression analysis was performed to calculate odds ratios (OR) and 95% confidence intervals (CI). Increased risks of gastric cancer were found for smokers (OR = 3.1, CI = 1.9–5.1 for pack-years ≥40 versus never smokers) and subjects with low fruit intake (OR = 2.2, CI = 1.3–3.6 for 1st versus 4th quartile); risk associated with vegetable intake was not statistically significant. Allele frequencies among the controls were consistent with those previously reported for the 5 polymorphisms studied: XRCC1-Arg399Gln, XPD-Lys751Gln, MGMT-Ile143Val, Leu84Phe, and XRCC3-Thr241Met. None of the studied polymorphisms were independently associated with gastric cancer risk. Smoking-associated risks, however, were greatest for carriers of the XRCC1-399 ArgArg genotype (Pinteraction = 0.004). Risks associated with low intake of fruits or vegetables tended to be modified by selected polymorphisms in XRCC1, XPD and MGMT (Pinteraction = 0.1–0.2). Risk modification was not found for the other repair polymorphisms. Selected DNA repair polymorphisms did not have independent effects on gastric cancer risk; however, they may modify smoking- and probably diet-related risks for this disease. These results need replication in larger epidemiological studies of gastric cancer.

Abbreviations: hME, homogeneous Mass Extend; MALDI-TOF MS, Assisted Laser Desorption Ionization-Time of Flight mass spectrometry; SNPs, single nucleotide polymorphisms; ROS, reactive oxygen species


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Gastric cancer is one of the most common cancers and causes of cancer death in Poland (1); multiple environmental and lifestyle factors may play a role (2), including tobacco use (3,4), a diet poor in fresh fruits and vegetables or rich in salt (5,6), and Helicobacter pylori infection (7,8). Our interest is in gastric carcinogenesis due to exogenous factors that cause DNA damage and cancer (i.e. tobacco use) or prevent these effects (i.e. fruits and vegetables), and their interrelationship with potentially risk modifying polymorphic variants in DNA repair genes involved in the repair of exogenously-induced damage (9).

Multiple DNA repair pathways exist providing distinct but overlapping protection against DNA-damaging exposures. Enzymes in base excision repair (e.g. XRCC1), remove simple base modifications, such as single-strand breaks, non-bulky adducts, oxidative DNA damage, alkylation adducts and damage induced by ionizing radiation (10,11). Nucleotide excision repair enzymes (e.g. XPD/ERCC2) remove more complex, bulky lesions, often caused by environmental agents (e.g. polycyclic aromatic hydrocarbons and arylamines) or UV light (12,13); but also have been associated with the repair of oxidative stress (14,15). Mismatch repair removes mispaired bases, small loops, and small deletions generated during DNA replication and recombination (16,17). Methyl (and ethyl) transferase enzymes (e.g. MGMT/AGT) reverse rather than excise DNA damage, by transferring methyl (and ethyl) groups from the O6 position of guanine to a specific cysteine residue of the transferase enzyme (18,19). XRCC3 acts in the homologous recombination repair of DNA double-strand breaks, generated by replication errors and endogenous and exogenous agents (20,21).

Since tobacco smoke is a rich source of reactive oxygen species (ROS) (22,23) and chemical carcinogens leading to DNA oxidative damage, PAH adducts, and alkylation adducts (24), the DNA repair pathways of ROS-induced double strand break repair, base excision repair, nucleotide excision repair, and alkyl (methyl and ethyl) transferase may be of particular importance to smoking-related gastric cancers. Since fruits and vegetables have high antioxidant properties and folate content, respectively, they can neutralize DNA-damaging free-radicals (25,26) and act as mediators of the methyl group transfer (27). These capacities may interact with DNA repair enzymes involved in base-excision, nucleotide excision, and double strand repair or with the MGMT/AGT alkyl transferases.

Polymorphic variants have been identified in a series of DNA repair genes (2830) and some are suspected risk factors for gastric (i.e. XRCC1) (3133) and other cancers (i.e. XRCC1, XPD, XRCC3) (21,24,3439). To expand our understanding of the role DNA repair polymorphisms play in gastric carcinogenesis, we studied common non-synonymous single nucleotide polymorphisms (SNPs) in four DNA repair genes (i.e. XRCC1, XPD, MGMT and XRCC3), representing four repair pathways, in relation to gastric cancer risk, in a population-based case-control study of gastric cancer in Warsaw, Poland.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study population
Design details of this population-based, case-control study of gastric cancer in Warsaw, Poland, are presented elsewhere (3). Briefly, residents of Warsaw, aged 21 to 79 years, who were newly diagnosed with a first gastric cancer (International Classification of Disease for Oncology: ICD-O 151 or ICD-O-2 C16) between March, 1994 and April, 1996, were eligible as cases. All cases were gastric adenocarcinoma and were identified through collaborating physicians in 22 hospitals and 8 private endoscopic units serving the study area and by regular reviews of the Cancer Registry files to ensure completeness of case ascertainment. Pathologic slides were obtained and reviewed in a standard fashion to confirm the diagnosis. Controls were frequency-matched to cases by sex and 5-year age groups, randomly selected from a computerized registry of Warsaw residents, which was updated monthly with nearly 100% registration completeness. Written informed consent was obtained from all participants and the study was approved by the Institutional Review Boards at the U.S. National Cancer Institute (NCI), Bethesda, Maryland and the Cancer Center and M. Sklodowska-Curie Institute of Oncology, Warsaw, Poland.

Data collection
Information was obtained through in-person interviews on demographic background, use of tobacco, alcohol and other beverages 2 years prior to interview, usual diet prior to 1990, lifetime occupational history, family history of cancer and personal history of selected medical conditions. Among eligible cases (n = 515) and controls (n = 549), successful interviews were conducted for 464 cases (90%; 324 direct interviews and 140 next-of-kin interviews, for deceased cases) and 480 (87%) controls. DNA was extracted from buffy coat isolated from a 30-ml blood sample or from pathology samples (98:2), resulting in 281 (61%) cases and 390 (81%) controls available for DNA-based analyses.

Genotype assay
Five DNA repair SNPs were studied: XRCC1 codon 399 (Arg to Gln, base pair 28152 G to A, exon 10, 19q13.2), XPD codon 751 (Lys to Gln, bp 35931 A to C, exon 23, 19q13.2-3), MGMT codon 143 (Ile to Val, bp 74091 A to G, exon 5, 10q24.33), MGMT codon 84 (Leu to Phe, bp 16282 C to T, exon 3, 10q24.33) and XRCC3 codon 241 (Thr to Met, bp 18067 C to T, exon 7, 14q32.3). These SNPs were analyzed using Assisted Laser Desorption Ionization-Time of Flight mass spectrometry (MALDI-TOF MS) and homogeneous MassExtend (hME) chemistry (Sequenom Inc., San Diego, CA). Two MALDI-TOF/hME multiplex assays that included the five SNPs were optimized according to optimum assay partners, reaction terminator mixes and suitable primers both for genomic polymerase chain reaction (PCR) amplification of the SNP-containing sequences and DNA polymerase extension within the optimal mass range of 5000–8500 Da. Desalted PCR and extension oligonucleotides were obtained from Integrated DNA Technologies (Coralville, IA).

The hME procedure comprising amplification, dNTP removal and extension reactions was performed using the SpectroDesigner Software (Sequenom Inc.) for assay design. The PCR amplification cocktail was composed of 1x AmpliTaq Buffer, 2.5 mM MgCl2, 115 µM dNTPs, 3–5 ng DNA template and 0.1 U of AmpliTaq Gold DNA polymerase. Forward and reverse primers were both at a 100 nM final concentration in a total reaction volume of 6.6 µl. PCR cycling was carried out in an MJ Research thermal cycler (Watertown, MA) with a 15-min denaturation step at 95°C, followed by 44 cycles of 20 s at 95°C, 30 s at 62°C, 1 min at 72°C and one last cycle of a 3 min hold at 72°C. Amplification was verified by running 1 µl of product on a 2% agarose gel. Non-incorporated dNTPs were removed by incubating the remaining amplification product at 37°C for 20 min in the presence of 0.5 U shrimp alkaline phosphatase, followed by 5 min at 85°C. Extension reactions were carried out on an MJ Research thermal cycler by adding 0.6 µM extension primer, 0.5 U Thermo Sequenase and a dideoxy/deoxy nucleotide mixture of ddATP, ddCTP, ddTTP and dGTP, at 50 µM each. The following extension cycling conditions were used: 2 min at 95°C, followed by 55 cycles of 5 s at 94°C, 5 s at 52°C and 5 s at 72°C. Extension products were desalted with SpectroClean Resin according to the manufacturer (Sequenom Inc.). The 384-element Matrix preloaded Spectro chips from Sequenom, Inc. (San Diego, CA) were spotted with ~15 nl of sample supernatant with a SpectroJet piezoelectric nanoplotter. MALDI-TOF mass spectrometry was carried out on a Bruker MALDI-TOF Biflex III instrument. Data acquisition and mass spectrometry, and genotyping were collected in an Sequenom SpectroTYPER RT workstation (Sequenom Inc., San Diego, CA).

Data analysis
We defined subjects who smoked at least one cigarette per day for 6 months or longer as smokers. Those who stopped smoking within the previous 2 years were considered current smokers. Cigarette pack-years were computed by multiplying packs of cigarettes smoked per day by the total years of smoking. For diet assessment, nutrient content of each food item was estimated using both US (40) and Polish food tables (41), with reference to original recipes for several unique Polish complex dishes (42). Gender-specific portion sizes were based on the POL-MONICA database (43) and DIETSYS portion sizes for food items that were unavailable in the POL-MONICA dataset (6).

Gastric cancer risk was estimated by calculating odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression. All analyses were adjusted for age, gender and smoking history (non-smoker, pack-years <40 and pack-years ≥40). Analyses involving dietary intake were additionally adjusted for total caloric intake from food (quartiles). Adjustments for additional suspected confounders, including education, first-degree family history of gastric cancer, red meat intake and years lived on a farm, led to no change in results and are not presented here. We performed trend tests for the three-level genotypes, cigarette use, and fruit and vegetable intake using logistic regression models based on the integer score (0,1,2). The effects of combined genes and exposures were examined by fitting a multiplicative model containing main effects and their cross-product terms, adjusted for confounders, with the inference based on the likelihood ratio statistic. All P values were two-sided. Individuals with missing values were excluded from specific analyses.

For genotype data, departure from Hardy–Weinberg equilibrium was assessed by comparing the expected genotype frequencies based on reported allele frequencies to the observed genotype frequencies. We estimated MGMT haplotypes defined by the codon 143 and 84 variants using HaploScore (44) and SAS/Genetics (45). Assessment of gastric cancer risk by haplotype for the two markers provides similar results to the individual genotype findings, and are not presented here.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Distributions of study cases and controls were similar with respect to the matching factors of age (12%, <50 years; 17%, 50–59 years; 39%, 60–69 years; and 32%, ≥70 years) and gender (66% males and 34% females). Cases tended to be more likely to have had a first-degree family history of gastric cancer (13% versus 4%, Px2 = 0.2) and had lower education (20% versus 31% of controls completed college, Px2 = 0.003). Similar demographic and lifestyle factors were observed among cases and controls with and without DNA samples (e.g. age, gender, education, smoking and intake of fruits and vegetables (Px2 > 0.05). Exclusion of data from subjects with DNA derived from tissue (2%) did not affect the results (data not shown).

In the case-control group for genotype analyses, gastric cancer risks increased with increasing cigarette use, rising to a 3-fold risk among those who smoked ≥40 pack-years (OR = 3.1, 95% CI = 1.9–5.1; Ptrend < 0.0001; Table I). Excess risk was found for both former smokers and current smokers (data not shown). Lower intake of fruits (1st versus 4th quartile) was also associated with an increased risk (OR = 2.2, 95% CI = 1.3–3.6; Ptrend = 0.005). Risk associated with vegetable intake was not statistically significant (Ptrend = 0.2).


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Table I. Gastric cancer risks associated with smoking and fruit and vegetable intake, Warsaw, Poland, 1994–1997

 
Among controls, the distributions of the XRCC1-399, XPD-751, MGMT-143, MGMT-84 and XRCC3-241 genotypes were consistent with the Hardy–Weinberg equilibrium, with allelic frequencies similar to those observed in other studies of Caucasians (21,38,39,46,47). None of the polymorphic variants in this series of DNA repair genes was associated with gastric cancer risk (Table II). However, homozygous carriage of the XRCC1-399 minor allele (GlnGln) was associated with increased risk in women (compared with ArgArg, OR = 2.3, 95% CI = 1.0–5.1) and decreased risk in men (OR = 0.6, 95% CI = 0.3–1.3). Most of the men in this population were smokers (87%), while fewer women smoked (43%); we further evaluated the genotype effects by smoking status.


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Table II. Gastric cancer risks associated with DNA repair polymorphisms, Warsaw, Poland, 1994–1997

 
The increasing gastric cancer risk associated with greater tobacco use (pack-years) was more pronounced among XRCC1-399 ArgArg than among ArgGln and GlnGln carriers (Pinteraction = 0.004, Table III). Similarly, a significant trend of increasing risks associated with recent smoking (i.e. never, former, current smoking) was found only among XRCC1-399 ArgArg carriers (Pinteraction = 0.0001, data not shown in Table III). Also, increased risk associated with the XRCC1-399 Gln carriers was found only among non-smokers (compared with ArgArg, OR = 2.5, 95% CI = 1.4–4.4). Similar patterns of smoking-related risks by genotype subgroups were found for men and women (data not shown). No modification of smoking-related risk was seen with polymorphic variants in genes coding for other DNA repair enzymes.


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Table III. Gastric cancer risks associated with joint effects of DNA repair polymorphisms and smoking, Warsaw, Poland, 1994–1997

 
Gastric cancer risks related to low fruit intake tended to be stronger for carriers of XPD-751 Gln or MGMT-143 Val and risks related to low vegetable intake tended to be stronger for XRCC1-399 ArgArg carriers, but tests for interaction were not statistically significant (Pinteraction = 0.1, 0.2 and 0.1, respectively, Table IV).


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Table IV. Gastric cancer risks associated with joint effects of DNA repair polymorphisms and fruit and vegetable intake, Warsaw, Poland, 1994–1997

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
In this population-based case-control study in Poland, we found no overall effect on gastric cancer risk of non-synonymous polymorphisms in genes coding for selected DNA repair proteins, XRCC1, XPD, MGMT, and XRCC3. Risks were greatest, however, in smokers with the XRCC1-399 ArgArg genotype. Risks tended to be greater in low fruit consumers who carried the MGMT-143 ValVal/IleVal or the XPD-751 GlnGln/LysGln genotypes and in low vegetable consumers who carried the XRCC1-399 ArgArg genotypes.

Previous findings for DNA repair polymorphisms and gastric cancer risks were scant and have not been entirely consistent. Unlike our findings, the XRCC1-399 Gln variant was associated with a marginally increased risk of gastric cancer in a Chinese population (188 cancer patients), with no apparent risk difference found between smokers and nonsmokers (32). Similar to our findings, the XRCC1-399 variant was not independently associated with gastric cancer risk in a Korean population (190 cancer patients), but risk pattern by smoking behavior was not evaluated in their study (31). Furthermore, consistent to our data, no association was found for the XRCC3-241 polymorphism and gastric cancer risk in a Chinese population (188 cancer patients), nor were the risk patterns differed by smoking status (33). Future large epidemiologic studies of gastric cancer are needed to clarify the role of XRCC1 gene variants and their potential interrelationships with cigarette smoking, evaluated in the context of a better characterized gene haplotype structure (rather than one SNP at a time) for each ethnic group. Smoking-specific and tumor tissue-specific functional patterns in association with a better characterized XRCC1 haplotype structure also may help clarify our understanding.

No previous studies of gastric cancer have examined the potential interrelationships between DNA repair gene polymorphisms and fruit and vegetable intake. There is substantial evidence that fruit and vegetable intake reduces risk for gastric cancer (26), possibly due to antioxidant activity neutralizing DNA-damaging free radicals and inhibiting formation of N-nitroso compounds (25,26), or through the action of folate and other B vitamins on genetic stability (27). In our data, increased gastric cancer risks associated with low fruit and vegetable intake were somewhat stronger for carriers of XRCC1-399 ArgArg, XPD-751 GlnGln/LysGln, and MGMT-143 ValVal/IleVal genotypes. The most promising results for the interrelationships between DNA repair polymorphisms and dietary nutrients were reported previously for other cancer sites. For example, low intake of dietary antioxidants was associated with an increased risk of prostate cancer only among XRCC1-399 ArgArg carriers (48). Also, a study of lung cancer (15) reported an increased risk associated with low intake of alpha-tocopherol supplement among XPD-751 GlnGln/LysGln carriers. Moreover, an increased risk of lung cancer was found for individuals who consumed low amount of cruciferous and green vegetables and carried the MGMT-143 Val allele (49),

A potential limitation of this analysis was the exclusion of cases (39%) and controls (19%) without DNA specimens. Further, a higher percentage of the cases excluded (62%) had advanced stage gastric cancer (i.e. distant metastasis) than the cases included (36%). This, however, was not expected to substantially impact the patterns of our results. First, similar demographic and lifestyle factors were observed among cases and controls with and without DNA samples (Px2 > 0.05), and the allelic frequencies we observed among controls were consistent with those reported for Caucasians by others (21,38,39,46,47). In addition, we obtained similar results including the distant metastasis cases only (data not shown) as opposed to all cases.

There is a likelihood of chance findings for the subgroup analyses. We had low statistical power to detect interactions between genotypes and smoking or fruit and vegetable intake. The inconsistent risk patterns we observed by gender for the XRCC1-399 variant appeared to be explained by smoking behavior. It is unclear, however, why the XRCC1-399 variant showed opposite effects for gastric cancer risk between smokers and non-smokers in our data. Data supporting our findings were available from epidemiological (46,50) and functional (51) studies, but there were conflicting results (15,52,53). It is interesting that we found strongest gastric cancer risks for both heavy smokers and low vegetable consumers, who were XRCC1-399 ArgArg carriers, perhaps suggesting coordinated mechanisms in play.

In summary, as an attempt to explore the role of DNA repair polymorphisms in various pathways for gastric carcinogenesis, we found no independent effect of the studied DNA repair variants in this population-based case-control study of gastric cancer in Poland. However, we found that smoking-related risk was most profound for carriers homozygous for the XRCC1-399 Arg allele, and some evidence that elevated risk related to low fruit or vegetable intake were stronger for carriers of XRCC1-399 ArgArg, XPD-751 GlnGln/LysGln and MGMT-143 ValVal/IleVal genotypes. Although these statistical associations had biological supports, confirmation by further investigations is needed to preclude chance findings. Progress on our understanding of the importance of the DNA repair polymorphisms in gastric carcinogenesis can be advanced by construction of risk-relevant haplotypes considering multiple loci in important genes, replication of findings in large epidemiological studies and sound functional data.

Conflict of Interest Statement: None declared.


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received November 3, 2004; revised March 18, 2005; accepted March 25, 2005.





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