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Carcinogenesis Advance Access originally published online on October 13, 2006
Carcinogenesis 2007 28(3):665-671; doi:10.1093/carcin/bgl160
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The association of sequence variants in DNA repair and cell cycle genes with cancers of the upper aerodigestive tract

Janet Hall1,10, Mia Hashibe1, Paolo Boffetta1, Valerie Gaborieau1, Norman Moullan1, Amelie Chabrier1, David Zaridze2, Oxana Shangina2, Neonila Szeszenia-Dabrowska3, Dana Mates4, Vladimir Janout5, Eleonóra Fabiánová6, Ivana Holcatova7, Rayjean J. Hung1,8, James McKay1, Federico Canzian1,9 and Paul Brennan1,*

1 International Agency for Research on Cancer Lyon, France
2 Cancer Research Centre Moscow, Russia
3 Institute of Occupational Medicine Lodz, Poland
4 Institute of Hygiene, Public Health, Health Services and Management Bucharest, Romania
5 Faculty of Medicine, Palacky University Olomouc, Czech Republic
6 Specialized State Health Institute, Banská Bystrica Slovakia
7 Institute of Hygiene and Epidemiology, Prague, Czech Republic CA, USA
8 School of Public Health, University of California at Berkeley CA, USA
9 German Cancer Research Center (DKFZ), Heidelberg Germany
10 Institut Curie, Centre de Recherche, Orsay France

*To whom correspondence should be addressed at: Genetic Epidemiology Group, International Agency for Research on Cancer, 150, cours Albert Thomas, 69372 Lyon, France. Tel: +33 4 72 73 8391; Fax: +33 4 72 73 84 32; Email: brennan{at}iarc.fr


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Supplementary data
 References
 
Cancers of the upper aerodigestive tract (UADT), comprising the oral cavity, pharynx, larynx and oesophagus, account for 5.2% of all cancers cases worldwide. The major risk factors, tobacco and alcohol can directly or indirectly generate DNA damage, which if unrepaired can give rise to mutations, unregulated cell growth and apoptosis induction. To clarify the role of DNA repair and cell cycle control proteins in UADT cancer susceptibility, we studied the risk in relation to 28 SNPs in 18 DNA repair enzymes and 9 SNPs in 7 cell cycle control genes. A case-control study was conducted from 2000 to 2002 in six centers from Romania, Poland, Russia, Slovakia and the Czech Republic. Patients diagnosed with squamous cell carcinoma of the UADT (n = 811) and controls with a recent diagnosis of diseases unrelated to tobacco and alcohol (n = 1083) were recruited. For UADT cancer risk, associations were observed for the homozygous carriers of the variant alleles of MGMT L84F [odds ratio (OR) 2.35, 95% confidence interval (CI) 1.32–4.20], MGMT 171C > T (OR 2.24, 95% CI 1.20–4.17) and OGG1 S326C (OR 2.07, 95% CI 1.15–3.73) whilst three variants were associated with a protective effect (XPA 23G > A, P for trend 0.022, APEX Q51H, P for trend 0.036, CHEK2 intron 9-200T > C, P for trend 0.009). Several other sequence variants showed associations with specific cancers without an overall association with UADT cancer. While some of these associations are consistent with previous studies, we cannot rule out the possibility of false-positive associations. The positive findings should be explored in another large-scale study on UADT cancers.

Abbreviations: UADT, upper aerodigestive tract; BER, base excision repair; FPRP, false-positive report probability; OR, odds ratio; CI, confidence interval


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Supplementary data
 References
 
Tobacco and alcohol consumption represent important risk factors for cancers of the upper aerodigestive tract (UADT), with evidence of a synergistic interaction (1,2). These agents directly or indirectly can generate DNA damage including modified DNA bases and strand breaks, which if unrepaired could give rise to mutations, unregulated cell growth and cancer, or apoptosis induction. Several DNA damage detection and repair pathways exist in mammalian cells, which initiate repair processes whilst blocking cell cycle progression and thus minimizing replication in the presence of DNA damage. The majority of these pathways involve several proteins that function in a coordinated fashion to remove and replace the damaged nucleoside residues. A growing body of literature suggests that reduced DNA repair capacity is associated with altered cancer risk and that genetic variations in DNA repair genes may alter the functional properties of DNA repair enzymes and are associated with modified cancer risk (3–5). The association between the presence of sequence variants in genes from several different DNA repair pathways and the risk of UADT cancer has been investigated in a number of case-control studies, although it should be noted that the statistical power of these studies is often limited by the small number of subjects investigated (6).

The inability of a cell to properly regulate its proliferation in the presence of DNA damage would also increase the risk of the accumulation of gene mutations. The transitions between different phases of the cell cycle are driven by changes in cyclin–cyclin-dependent kinase (CDK) pairs. To ensure the completion of each phase before entry into the next, surveillance mechanisms or cell cycle checkpoints monitor the process. If errors or defects are detected, progression is reversibly halted by CDK inhibitors. Genetic variations in cell cycle control genes, such as those found in the CHEK2 kinase, have also been shown to impact on cancer risk (7) and a few case-control studies have explored the association between sequence variants in cell cycle control genes and head and neck cancer; however their statistical power is often limited (6).

To clarify the role of DNA repair enzymes and cell cycle control proteins in the susceptibility to head and neck cancer we studied the risk in relation to 28 variants in 18 DNA repair enzymes [base excision repair (BER)—8 variants/5 enzymes, nucleotide excision repair (NER)—11 variants/7 enzymes, O6-methylguanine-DNA-methyltransferase (MGMT)—4 variants, double-strand break repair—3 variants/3 enzymes, mismatch repair—2 variants/2 enzyme] and 9 variants in 7 cell cycle control genes in 811 UADT cases and 1083 controls. The variants were selected as part of a comprehensive review of genes with either epidemiological or functional evidence of an association with head and neck cancer (8), inclusion in the SNP500 project (http://snp500cancer.nci.nih.gov), or based on their location promoter or coding regions and with minor allele frequencies of at least 5% in Caucasian populations.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Supplementary data
 References
 
A multicenter case-control study was conducted in six centres from five Central and Eastern European countries: Bucharest (Romania), Lodz (Poland), Moscow (Russia), Banska Bystrika (Slovakia), and Olomouc and Prague (Czech Republic) (9). The overall recruitment period at the centres was from 2000 to 2002. UADT cancer cases diagnosed at designated hospitals or cancer clinics and confirmed histologically or cytologically were recruited into the study within 3 months of diagnosis. Of the 906 UADT cancer cases who were interviewed, 811 subjects provided blood samples from which DNA was extracted and analysed. These 811 UADT cancer cases included 168 oral SCC cases, 113 pharyngeal SCC cases, 326 laryngeal SCC cases and 176 oesophageal SCC cases. An additional 28 of oral and pharyngeal SCC whose site was unspecified or overlapping, were included in the overall UADT cancer case group.

Controls, with a recent diagnosis from a defined list of diseases unrelated to tobacco and alcohol, were randomly chosen from in-patients or out-patients in the same hospital as the cases. The distribution of control diseases were 11% of the musculoskeletal system, 11% genitourinary, 10% skin, 9% gall-bladder or biliary tract, 8% CNS, 8% eye, 7% circulatory system, 5% other digestive, 5% hernias, 3% injury/poisoning, 2% metabolic, 2% appendicitis, 2% mental, 2% respiratory and 14% other diseases. In Moscow, the controls were frequency matched to the UADT cancer cases by age, sex, and referral or residence area. In the other centers, controls overlapped with those for a parallel case-control study of lung cancer conducted according to an identical protocol and were frequency matched with cases on age, sex and center (9–12). Of the 1352 controls recruited and interviewed, 1083 gave blood that resulted in successful DNA extraction. Since the lung cancer study was started earlier than the UADT cancer study, we excluded controls if their interview date was more than 6 months earlier than the first interview date for the UADT cancer cases. Written consent for participation was obtained from all study subjects and ethical approval has been obtained for all study centres and IARC. Cases and controls were interviewed with a structured questionnaire on residential and lifestyle history by the same team of interviewers in each centre.

Genomic DNA was extracted from blood samples with the use of a QIAamp 96 DNA Blood Kit (Qiagen, Hilden, Germany), or with Puregene chemistry (Gentra Systems, Minneapolis, MN) on an Autopure instrument (Gentra Systems). Samples that yielded an insufficient amount of DNA at extraction were subjected to whole genome amplification by use of a phi29-based protocol (GenomiPhi, Amersham Biosciences, Uppsala, Sweden) or re-extracted using Gentra technology. DNA concentrations were measured by using PicoGreen dsDNA quantification kits (Molecular Probes, Leiden, The Netherlands).

Of the 37 SNPs genotyped (Supplementary Table I) 33 polymorphisms were analysed by the 5' exonuclease assay (i.e. TaqMan assay) (13), 1 using the allele-specific PCR-based Amplifluor assay (XRCC1 R399Q rs25487) (14) and 2 using the MGB Eclipse Probe System (P73 C14T, rs1801173: MLH1 I219V, rs179977) (15). In addition the presence of the TP53 intron 3 16 bp duplication was assessed using a gel based discrimination assay. Designs of genotyping assays for the SNPs were either taken from the website of the SNP500 project (http://snp500cancer.nci.nih.gov) or were designed by Applied Biosytems (Foster City, CA) or Proligo (Paris, France) or in house using the GeneBank databases and Primer Express (Applied Biosystems). PCR primers and TaqMan probes were synthesized by Applied Biosystems or Proligo. Eclipse probes were obtained from Nanogen (San Diego, CA) and Ampliflour probes from Serologicals Corporation (Norcross, GA). Briefly, 10 ng aliquots of genomic DNA were placed into separate wells of a 96-well or 384-well PCR plate along with a PCR cocktail that included fluorescently-labelled allele-specific probes. The fluorescence of the PCR products was then plotted and genotype was determined according to the signal of the two probes. The TP53 intron 3 16 bp duplication was genotyped by PCR, with the A1 and A2 alleles giving a band size on 2% agarose gel of 114 and 130 bp, respectively. Details of primers, probes and protocols for all genotyping are available upon request.

To ensure quality control, DNA samples from case patients and control subjects were randomly distributed on each PCR plate, and all genotyping was conducted by personnel who were blinded to the case or control status. We randomly selected 10% of the study subjects (i.e. both case patients and control subjects) and re-analysed their DNA samples for each polymorphism to examine the reliability of the genotyping assays. We also assessed Hardy–Weinberg Equilibrium in the controls for each genotype.

Statistical analysis
Tobacco smoking included smoking of cigarettes, pipes and/or cigars. Former smokers were defined as smokers who quit smoking at least 2 years prior to interview or diagnosis. Cumulative tobacco consumption was calculated as the product of smoking duration (years) and intensity (packs per day) and expressed as packyears.

Hardy–Weinberg equilibrium of allele distributions was tested in cases and in controls separately. We used unconditional multivariate logistic regression to assess the main effects of genetic polymorphisms on risk by estimating odds ratios (OR) and associated confidence intervals (CI). Genotypes were categorized into three groups when the allele frequencies allowed (major allele homozygous, heterozygous and homozygous variant).

We conducted stratified analyses by tumour site to investigate the effect of genetic polymorphisms. The following variables were included in the logistic regression model for adjustment: country of residence, age (continuous), sex, smoking in packyears (continuous) and duration of alcohol consumption. For subjects who were missing information on packyears of smoking or alcohol consumption (35 cases and 85 controls), we imputed the median of these variables in the controls. The false-positive report probability (FPRP) for statistically significant observations was estimated using the methods described by Wacholder et al. (16).


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Supplementary data
 References
 
The study population characteristics are shown in Table I. The age distribution was fairly similar among cases and controls with a higher proportion of women in the control group compared to the cases. Comparing cases and controls on demographic/lifestyle variables, as expected, smoking and drinking prevalence were higher among cases.


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  		Table I Study population characteristics

 
The frequency of 37 sequence variants was assessed in DNA samples from 811 cases and 1083 controls. The percentage of undetermined genotypes was below 5% for all the variants examined except three (MSH6 D180D, XPD D312N and TP53 intron 3 duplication) and all variants reached >99% genotyping repeatability. The TP53 intron 3 duplication proved the hardest genotype to determine with the gel based assay showing the highest level of inconsistency (1%) and the highest level of undetermined genotypes (6.34%). The genotype distributions in the control subjects were in Hardy–Weinberg equilibrium.

Odds ratios for the six sequence variants for which a main effect on the risk of UADT cancer and by cancer site, adjusted for age, sex, country, smoking (packyear) and years of alcohol drinking are presented in Table II. The variant alleles of MGMT at position C171T and L84F and OGG1 at S326C were associated with an increased risk of UADT cancer when present in the homozygous state (MGMT 171 TT versus CC OR 2.24, 95% CI 1.20–4.17, MGMT 84 FF versus LL OR 2.35, 95% CI 1.32–4.20, OGG1 326 CC versus SS OR 2.07, 95% CI 1.15–3.73). Three variants were associated with a protective effect. The A allele at position 23 of XPA (P for trend 0.022) and the H allele at position 51 of APEX (P for trend 0.036) and the CHEK2 intron 9 variant (P for trend 0.009). Data for the other variants examined are available in Supplementary Table II and on the International Head and Neck Cancer Epidemiology (INHANCE) consortium website (http://inhance.iarc.fr).


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  		Table II DNA repair/cell cycle SNPs and the risk of head and neck cancer (for SNPs where an association may exist)

 
For individual cancer sites an increased risk of oesophageal cancer was seen for homozygous carriers of the MGMT 171T and L84F alleles (TT versus CC OR 3.42, 95% CI 1.48–7.88 and FF versus LL OR 3.27, 95% CI 1.43–7.52, respectively) and an increased risk of laryngeal cancers in the homozygous carriers of L84F alleles (FF versus LL OR 2.30, 95% CI 1.11–4.77).

The OGG1 326C allele showed an association with both oral (CC versus SS OR 3.71, 95% CI 1.52–9.04) and pharynx cancers (CC versus SS OR 3.34, 95% CI 1.11–10.09). The XPA 23A variant allele appeared to be associated with a protective effect in pharynx cancer, though only among the heterozygotes (GA versus GG OR 0.61, 95% 0.38–0.98). The CHEK2 intron 9 variant showed significant associations with altered oral and laryngeal cancer risks (P for trend = 0.043 and 0.027, respectively). Several other sequence variants showed associations with altered risk of developing one or more of the specific cancers investigated although no overall association was noted. For the other SNPs in DNA repair and cell cycle control genes no statistically significant associations were observed in the present study. Table III is the FPRP for the statistically significant results we observed. Assuming a relatively strong prior for the variants in MGMT, XPA and OGG1 reported and an intermediate prior for CHEK2, the FPRP support these observations. We feel that the functional significance of these variants and previous association studies justifies such priors. However for the APEX Q51H variant there is little published data and a lower prior probability (e.g. 1–0.1%) might be more appropriate and thus the observed odds ratio may reflect a false-positive association.


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  		Table III False-positive report probability

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Supplementary data
 References
 
This study identified six sequence variants out of the 37 analysed that were associated with altered overall UADT cancer risk. Four of these SNPs were in DNA repair genes encoding a protein playing a role in the initial stages of a multi-step repair pathway or in the direct reversal of methylation damage by MGMT. This methyltransferase is the principal mechanism for repairing the promutagenic lesion O6-methylguanine formed by alkylating agents. Of the four SNPs in this gene studied, the homozygote carriers of the 171C > T and the L84F variants had an increased risk of head and neck cancer. These two variants have been reported to be in linkage disequilibrium (17) and in our study population the r2 is 0.91 (D' = 0.99). The L84F variant has been found to be associated with a decreased risk of head and neck cancer in a pooled analysis of 430 head and neck cases and 695 controls (18). In the same analysis, carriage of the MGMT 143Val allele was also associated with decreased risk of head and neck cancer. This is in contrast to the results obtained in our study where no altered risk was found. The reasons for these apparently conflicting results are unclear. From a mechanistic point of view the functional importance of these SNPs is unknown. The MGMT143 variant is close to the active site of the protein, Cys 145, and a recent paper by Hill et al. (19) suggests that the 84F and 143V SNPs may alter the function of the MGMT protein resulting in sub-optimal repair of genetic damage induced by NNK, the tobacco specific nitrosamine.

OGG1 is one of the >20 genes that participate in BER pathway and this DNA glycosylase repairs one of the most mutagenic lesions among base damages, 8-oxoG, formed following exposure to tobacco smoke. Conflicting results have been reported on the association of the OGG1 Cys326 allele and head and neck cancer risk (6,20–22). In this study this variant was associated with an increased risk in the overall analysis but this association was only significant for the homozygous carriers of the variant allele and not for the trend. For another smoking related cancer, an increased lung cancer risk among subjects carrying the OGG1 Cys/Cys genotype (OR =1.24, 95% CI = 1.01–1.53) based on a meta-analysis of 3253 cases and 3371 controls from seven studies was found (6), which is consistent with the experimental evidence that this isoform exhibits a decrease in 8-oxoG excision in human cells and a lack of stimulation by APEX1 (23), which is the major mammalian repair protein for abasic sites in DNA. Such lesions arise either spontaneously, via accelerated base release because of chemical modifications or following the action of DNA gycosylases in the BER pathway. Two APEX1 SNPS were examined in this study population. The D148E variant showed no association with UADT risk, although a protective effect was noted in young onset homozygous carriers of the Glu allele (OR 0.33, 95% CI 0.16–0.67). This result is in agreement with a meta-analysis of 1359 cases and 1686 controls from four studies where no association was seen between this allele and aerodigestive tract cancers (20). In contrast, the Q51H variant was associated with a reduced overall risk of UADT cancers. It should be noted however that based on the false-positive report probability and assigning a lower prior probability as the impact of this variant on enzyme function is not known and it has been studied in relatively few studies, this result may reflect a false-positive association. This variant has been studied in another smoking related cancer with no association of the variant allele being found with lung cancer risk [(24), Hung et al. manuscript in preparation]. None of the other variants studied in the BER pathway appeared to influence overall UADT cancer risk. The G23A in the XPA gene was also associated with a slight protective effect. The XPA protein is part of the damage recognition XPC–RPA protein complex and this polymorphism located within the Kozak sequence near the start codon may affect XPA protein levels in cells. A functional association between the variant and DNA repair capacity (DRC) has been found with control subjects with one or more copies of the G allele demonstrating more efficient DRC than those with the homozygous A allele (25). There are no previously published data on this SNP in relation to risk of developing UADT cancers but these results are consistent with those in lung cancer where several groups have reported that the G allele was associated with reduced risk (25–27).

Among the SNPs studied in cell cycle genes no association of the TP53 codon 72 variant and UADT cancer risk was noted which is consistent with eight other published studies. The TP53 int three duplication showed no main effect either; however an association was noted in oesophageal cancer. Several studies have correlated this duplication with an increased risk of various cancers but the results are sometimes inconsistent between tumour sites (28). Reduced levels of TP53 mRNA were associated with the allele carrying the duplication (29) but it is not known whether this impacts on the cellular response to DNA damage. The 309T > G variant in the MDM2 gene, whilst showing no main effect, was found to be associated with an altered risk of oesophageal cancers with an increased risk being seen in the homozygote carriers of this variant. The MDM2 gene product also plays a role in controlling p53 levels in cells and this SNP has been shown to modify a SPI-transcription factor binding site and raises the basal level of MDM2 in cells, which attenuates the p53 apoptotic response that occurs in response to DNA damage (30). Whilst oesophageal tumours share many of the aetiological factors common to all UADT tumours there may be differences in relation to endogenous and environmental risk factors and genetic susceptibility and it is interesting to note that variants in both the TP53 and MDM2 genes, which play a major role in the control of the cell cycle in response to DNA damage, are associated with an altered risk in esophageal tumours.

Of the other cell cycle variants examined, the intron 9 variant in CHEK2 studied here showed a significant association with altered risk. The CHEK2 gene encodes a multifunctional enzyme that plays a central role in the induction of cell cycle arrest and apoptosis by DNA damage (31). The first evidence that genetic alterations in CHEK2 may predispose to cancer came from studies on families Li-Fraumeni syndrome often linked to germline mutations in the p53 gene. A sub-set of families was identified containing a deletion mutation (1100delC) and a wild-type TP53 gene. This rare variant resulting in a premature protein truncation, has subsequently been found to confer increased breast and prostate cancer risk (7). Only one case and one control from our study population were found to be carriers of this mutation making it difficult to assess the UADT cancer risk conferred by this mutation. The more common missense variant I157T, has been found to associated with an increased risk of breast, colon, kidney, prostate and thyroid cancer leading to the suggestion that CHEK2 is a multi-site cancer gene (32). We found a protective effect for this variant for UADT and lung cancer (Brennan et al. manuscript submitted) suggesting that variants in this gene could be associated with increased or decreased cancer risk and that this may be a function of the selective pressures exerted on the cell and would be tissue specific. If the variant protein has an altered function and cell cycle control in the presence of DNA damage is abrogated, this might give rise to enhanced apoptosis at the time of cell division. Thus in dividing cells with the apoptotic machinery intact the variant allele would be associated with reduced cancer risk but in cells where the function of the apoptotic machinery is also abrogated its presence would be associated with an increased risk. In this study we have genotyped a polymorphism located in intron 9, which also showed an inverse association with risk, with the CC genotype being associated with a decreased UADT cancer risk. Interestingly, this effect cannot be explained by LD with the I157T polymorphism, indicating that other genetic variation on CHEK2 may be influencing risk.

A number of the SNPs investigated in this study have been examined previously in UADT/head and neck cancer association studies. For instance the XPD K751Q variant has been extensively studied with a recent pooled analysis of 555 head and neck cases and 792 controls finding no association of the XPD 751 variant with altered risk (18). Our results are consistent with this pooled analysis. Similarly three studies (including the present study) have now found no association of XRCC3 T241N with head and neck cancer risk (33,34), suggesting that this SNP is not associated with a significant risk of head and neck cancer. The association of Arg194Trp, Arg280His, Arg399Gln variants in XRCC1 with risk of tobacco-related cancers has not been consistent (4,6). The results from the present study suggest that the presence of variants in the XRCC1 gene do not have a major impact on UADT cancer risk.

In conclusion the results obtained from the present study, with adequate power for detecting modest effects of low-penetrance genes, would suggest that the focus of molecular epidemiology studies on head and neck cancer should change. Two of the SNPs showing an association with altered risk were in proteins involved in the initial steps of the repair processes. Further studies focusing on the enzymes involved in the recognition and removal of DNA adducts formed following tobacco and alcohol consumption, or DNA mismatches generated through the incorporation of oxidised deoxynucleotide tri-phosphates would seem appropriate. In addition, the strong associations noted with the CHEK2 variants, a protein that is activated in response to DNA damage and relays the signals between the damage detection kinases, such as ATM and ATR and downstream effectors would suggest that proteins involved in such signaling cascades warrant further investigation. For several of the SNPs studied associations were noted only for individual tumour sites, suggesting that specific endogenous and environmental risk factors may exist for certain sites in addition to those common to all UADT tumours. However, the numbers of observations in these are small and as multiple testing was carried out, the results should be considered as preliminary. Further validation of such findings by larger studies would allow more rigorous sub-group analysis and is clearly warranted.


   Supplementary data
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary data
References
 
Supplementary data are available at Carcinogenecis online.


   Acknowledgments
 
The authors thank Melissa Southey and Sean Tavtigian for their critical review and comments on the manuscript. The study was funded by a National Cancer Institute R01 grant (contract no. CA 092039-01A2). J.M. is a CJ Martin Research Fellow (NHMRC Australia).

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Supplementary data
 References
 

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Received May 22, 2006; revised August 3, 2006; accepted August 25, 2006.


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