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DNA repair genetic polymorphisms and risk of colorectal cancer in the Czech Republic


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Mutation Research 638 (2008) 146–153

Available online at www.sciencedirect.com

DNA repair genetic polymorphisms and risk of colorectal

cancer in the Czech Republic

B. Pardini


, A. Naccarati


, J. Novotny


, Z. Smerhovsky


, L. Vodickova



V. Polakova


, M. Hanova


, J. Slyskova


, E. Tulupova


, R. Kumar



M. Bortlik


, R. Barale


, K. Hemminki


, P. Vodicka


aDepartment of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic,

Videnska 1083, 14220 Prague 4, Czech Republic

bDepartment of Biology, University of Pisa, via S. Giuseppe, Pisa 56127, Italy

cDepartment of Oncology, General Teaching Hospital, U Nemocnice 2, 12808 Prague 2, Czech Republic dCentre of Occupational Health, National Institute of Public Health, Srobarova, 10042 Prague 10, Czech Republic eDivision of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Am Neuenheimer Feld 585, Heidelberg, FRG

fDepartment of Gastroenterology, General Teaching Hospital, U Nemocnice 2, 12808 Prague 2, Czech Republic Received 26 July 2007; received in revised form 20 September 2007; accepted 25 September 2007

Available online 2 October 2007


Colorectal cancer represents a complex disease where susceptibility may be influenced by genetic polymorphisms in the DNA repair system. In the present study we investigated the role of nine single nucleotide polymorphisms in eight DNA repair genes on the risk of colorectal cancer in a hospital-based case–control population (532 cases and 532 sex- and age-matched controls). Data analysis showed that the variant allele homozygotes for the Asn148Glu polymorphism in the APE1 gene were at a statistically non-significant increased risk of colorectal cancer. The risk was more pronounced for colon cancer (odds ratio, OR: 1.50; 95% confidence interval, CI: 1.01–2.22; p = 0.05). The data stratification showed increased risk of colorectal cancer in the age group 64–86 years in both individuals heterozygous (OR: 1.79; 95% CI: 1.04–3.07; p = 0.04) and homozygous (OR: 2.57; 95% CI: 1.30–5.06;

p = 0.007) for the variant allele of the APE1 Asn148Glu polymorphism. Smokers homozygous for the variant allele of the hOGG1

Ser326Cys polymorphism showed increased risk of colorectal cancer (OR: 4.17; 95% CI: 1.17–15.54; p = 0.03). The analysis of binary genotype combinations showed increased colorectal cancer risk in individuals simultaneously homozygous for the variant alleles of APE1 Asn148Glu and hOGG1 Ser326Cys (OR: 6.37; 95% CI: 1.40–29.02; p = 0.02). Considering the subtle effect of the DNA repair polymorphisms on the risk of colorectal cancer, exploration of gene–gene and gene–environmental interactions with a large sample size with sufficient statistical power are recommended.

© 2007 Elsevier B.V. All rights reserved.

Keywords: Colorectal cancer; Individual susceptibility; DNA repair; Single-nucleotide polymorphisms; Case–control study

Corresponding author. Tel.: +420 2 41062694; fax: +420 2 41062782.

E-mail address:pvodicka@biomed.cas.cz(P. Vodicka).

1. Introduction

Colorectal cancer (CRC) is a common neoplasia in both men and women, with an estimated lifetime risk of about 5% in the Western countries[1]. CRC ranks as the second most common type of cancer (11.5% world-0027-5107/$ – see front matter © 2007 Elsevier B.V. All rights reserved.


B. Pardini et al. / Mutation Research 638 (2008) 146–153 147

wide), with approximately 87,500 new cases diagnosed each year. An increase in the CRC incidence has been recorded all over Europe in the past decade, being par-ticularly severe in central European regions[2]. Despite increase in the incidence mortality rates in developed countries, probably due to early screening, have gradu-ally decreased[3]. CRC occurs in three specific settings: (a) sporadic form that accounts for over 85% of all cases, (b) familial form that constitutes less than 10%, and (c) inherited form with a clear Mendelian transmis-sion, observed in 5% of all cases, which include familial adenomatous polyposis (FAP), and hereditary non-polyposis colorectal cancer (HNPCC) syndromes[4].

Both environmental and genetic factors appear to have a consistent role on the onset of sporadic CRC. Diet, smoking and drinking habit are environmental fac-tors frequently associated with CRC risk[5,6]. However, a little is known about the mechanisms that contribute to the risk modulation [7]. It is likely that individ-ual genetic factors modulate risk of CRC [7]. This modulation can probably be attributed to the genetic variants with low penetrance, which in complex inter-actions influence the process of CRC development[8]. Genes implicated in metabolic pathways, methylation, immune response, oncogenes, tumor suppressor genes, genes modifying the colon microenvironment, as well as genes involved in the DNA repair, have been considered as possible candidates with a role in CRC susceptibil-ity[9]. DNA repair is a complex system of defenses evolved to protect the genomic integrity and involved in the process preventing carcinogenesis[10,11]. Interindi-vidual differences in DNA repair capacities are important determinants of cancer risk including CRC [12]. The polymorphisms in different DNA repair genes that are mainly represented by single-nucleotide polymorphisms (SNPs) can potentially modulate the individual DNA repair capacity [13,14] and therefore exert an impact on individual genetic susceptibility to a wide range of cancers. The main findings of the published studies on the effect of DNA repair genetic polymorphisms on the risk of cancer have been summarized in several reviews. Only in a few instances, consistent evidence for associa-tion of genetic polymorphisms with specific cancers has emerged[15–18]. In recent years, an increasing number of studies have investigated the role of polymorphisms in DNA repair genes on individual susceptibility to CRC with inconclusive outcomes[19].

The aim of the present study was to investigate the associations, if any, between polymorphisms in the genes involved in different DNA repair pathways and the risk of CRC in a population from the Czech Republic. CRC represents a major health issue in the country with the

third highest incidence rate in the world and the highest for the rectal cancer[2,20,21]. SNPs were selected on the basis of our recent investigations on functional effects on DNA repair capacities[13], DNA and chromosomal damage[22]in the healthy population from the same area.

2. Materials and methods

2.1. Study population

Cases and controls for this hospital-based study were collected at several oncological and gastroenterological depart-ments of different hospitals all over the Czech Republic. The study is based on incident cases recruited from Septem-ber 2004 to February 2006. Cases consist of patients with positive colonoscopic results for malignancy, histologically confirmed as carcinomas of colon or rectum. Controls included subjects undergoing colonoscopy for various gastrointestinal complaints and sampled at the same time as the cases. The con-trols were with negative colonoscopic results for malignancy or idiopathic bowel diseases. Five hundred and thirty-two CRC patients and 532 controls included in the present study were matched for sex and age. Structured questionnaire was used to get information from study subjects about lifestyle habits (smoking, drinking, diet, etc.), and family/personal his-tory of cancer. The genetic analyses did not interfere with diagnostic or therapeutic procedures for the subjects. An informed written consent was signed by all participants and the study design was approved by the Ethical Committee of the Institute of Experimental Medicine, Prague, Czech Republic.

2.2. Genotyping

DNA was isolated from coded blood samples and stored at −80◦C. SNPs in genes encoding various DNA repair enzymes were genotyped using either PCR-RFLP or TaqMan allelic discrimination assay. PCR for the XPD Lys751Gln (rs28365048), XPG Asn1104His (rs17655), XPC Lys939Gln (rs2228001), XRCC1 Arg194Trp (rs1799782) and Arg399Gln (rs25487), hOGG1 Ser326Cys (rs1052133),

XRCC3 Thr241Met (rs861539) polymorphisms was carried

out using primers and conditions described previously[13]. The amplified DNA fragments were digested with appropriate restriction endonucleases, resolved on 2% agarose gel and visu-alized under UV light after staining with ethidium bromide. The APE1 Asn148Glu (rs1130409) and NBS1 Glu185Gln (rs1805794) polymorphisms were analysed using the TaqMan allelic discrimination assay (Applied Biosystems, assay-on-demand, SNP genotyping products: C 26470398 10 for NBS1 and C 8921503 10 for APE1). The TaqMan genotyping reac-tion was amplified on a 7500 real-time PCR system (95◦C for 10 min, 92◦C for 15 s, and 60◦C for 1 min for 40 cycles). The genotype screening was performed simultaneously for cases and controls. The results were regularly confirmed by


ran-148 B. Pardini et al. / Mutation Research 638 (2008) 146–153

dom re-genotyping of more than 10% of the samples for each polymorphism analysed.

2.3. Statistical analyses

Differences in baseline sociodemographic characteristics between cases and controls were analysed using χ2-test. Genotype frequencies for each polymorphism were tested in controls for deviation from Hardy–Weinberg equilibrium, using Pearsonχ2-test. Odds ratio (OR), 95% confidence inter-vals (CIs) and p-values were determined by logistic regression to examine the association between each genotype and risk of CRC. The binary logistic regression model included age, gender and smoking information. Combinations of geno-types, selected from SNPs in genes of the same DNA repair pathway, were constructed and investigated for their possi-ble impact on CRC risk. Stratified analyses were conducted to evaluate effects of potentially modifying factors on the associations of interest-like age (the age groups based on tertiles of age distribution) and smoking status (smokers vs. non-smokers). All tests were two sided and performed at 5% level of statistical significance. Statistical calculations were performed using SPSS 13.0 for Windows (Chicago, IL, USA).

3. Results

The characteristics of the subjects involved in the study are reported in Table 1. There were no sig-nificant differences in all characteristics between the patients and controls. The only significant difference was a smaller proportion of females among patients with rectal cancer, as referred to the control popula-tion (χ2= 4.99 and p = 0.04), due to the higher incidence of rectal cancer in males and the primary match-ing for colorectal cancer as a whole. Distribution of genotypes for DNA repair gene polymorphisms was in Hardy–Weinberg equilibrium in controls, with

non-significant χ2 values (data not shown). The genotype distributions for both cases and controls are presented in

Table 2.

None of the studied polymorphisms was indepen-dently associated with CRC risk in either dominant or recessive model of inheritance (Table 2). Individ-uals homozygous for the variant allele for the APE1 Asn148Glu polymorphism exhibited an increased risk of CRC that was not statistically significant (OR: 1.39; 95% CI: 0.98–1.96). The analyses of specific cancer sites (Table 2) showed that the variant allele homozy-gous genotype for the APE1 Asn148Glu polymorphism was associated with an increased risk of colon cancer (OR: 1.50; 95% CI: 1.01–2.22; p = 0.05). When similar analyses were performed on patients with rectal cancer, no independent association with any polymorphism was found (Table 2).

3.1. Genotype combination interactions

Binary genotype combination interactions were tested for association with CRC risk for selected SNPs in genes involved in the same DNA repair pathway. We found significantly increased risk of CRC in individu-als carrying variant allele homozygous genotypes for both APE1 Asn148Glu and hOGG1 Ser326Cys poly-morphisms (OR: 6.37; 95% CI: 1.40–29.02; p = 0.02,

Table 3). The same genotype combination also showed an increased risk for colon cancer (OR: 7.14; 95% CI: 1.49–34.38; p = 0.01). Analysis showed that indi-viduals bearing XPD 751GlnGln and XPG 110HisHis genotypes in combination exhibited statistically non-significant increased risk for the rectal cancer (OR: 8.14; 95% CI: 0.87–86.36), however, there were only three individuals in cases and one person in controls.

Table 1

Distribution of CRC cases and healthy controls according to the gender, age at the diagnosis and smoking status

Controls (n = 532) All cases (n = 532) Colon cancer (n = 335) Rectal cancer (n = 197) Gender

Males 294 294 167 127

Females 238 238 168 70*

Age at diagnosis (years)

Mean± S.D. 57.4± 12.8 58.5± 10.5 58.5± 10.9 58.4± 9.7

Range 29–85 26–86 26–84 26–86

Smoking status

Non-smokers 71.7% (358) 73.2% (372) 75.6% (242) 69.1% (130)

Current smokers 28.3% (141) 26.8% (136) 24.4% (78) 30.9% (58)


B. P a rdini et al. / Mutation Resear ch 638 (2008) 146–153 149 Table 2

Distribution of DNA repair genotypes and results of unconditional logistic regression analysisa, considering all cases together or stratified for the specific site of cancer

Genotypes Controls (n = 532) Cases (n = 532) OR (95% CI) p-Value Colon (n = 335) OR (95% CI) p-Value Rectum (n = 197) OR (95% CI) p-Value Base-excision repair XRCC1 Arg194Trp ArgArg 466 454 1.00 288 1.00 166 1.00 ArgTrp 59 72 1.24 (0.86–1.80) 0.25 45 1.24 (0.82–1.88) 0.32 27 1.24 (0.76–2.03) 0.38 TrpTrp 5 6 1.17 (0.35–3.87) 0.80 2 0.61 (0.12–3.21) 0.56 4 1.92 (0.51–7.31) 0.34 ArgTrp + TrpTrp 64 78 1.24 (0.87–1.77) 0.24 47 1.19 (0.79–1.78) 0.41 31 1.30 (0.82–2.07) 0.27 XRCC1 Arg399Gln ArgArg 219 229 1.00 152 1.00 77 1.00 ArgGln 240 233 0.93 (0.72–1.21) 0.60 146 0.87 (0.65–1.16) 0.33 89 1.09 (0.76–1.56) 0.63 GlnGln 73 68 0.88 (0.60–1.29) 0.52 37 0.71 (0.45–1.11) 0.14 31 1.29 (0.78–2.12) 0.32 ArgGln + GlnGln 313 301 0.92 (0.72–1.18) 0.51 183 0.83 (0.63–1.09) 0.19 120 1.14 (0.81–1.59) 0.46 hOGG1 Ser326Cys SerSer 331 336 1.00 225 1.00 111 1.00 SerCys 181 168 0.91 (0.70–1.18) 0.47 90 0.73 (0.53–0.98) 0.03 78 1.29 (0.91–1.81) 0.15 CysCys 20 28 1.43 (0.79–2.59) 0.24 20 1.52 (0.80–2.91) 0.20 8 1.22 (0.52–2.86) 0.65 SerCys + CysCys 201 196 0.96 (0.75–1.23) 0.74 110 0.80 (0.60–1.07) 0.14 86 1.28 (0.92–1.79) 0.15 APE1 Asn148Glu AsnAsn 157 140 1.00 82 1.00 58 1.00 AsnGlu 267 261 1.10 (0.83–1.47) 0.50 171 1.22 (0.87–1.69) 0.25 91 0.96 (0.65–1.42) 0.85 GluGlu 106 130 1.39 (0.98–1.96) 0.06 82 1.50 (1.01–2.22) 0.05 48 1.24 (0.79–1.96) 0.35 AsnGlu + GluGlu 373 391 1.18 (0.91–1.55) 0.22 153 1.30 (0.95–1.77) 0.10 139 1.05 (0.73–1.50) 0.81 Nucleotide-excision repair XPD Lys751Gln LysLys 174 189 1.00 118 1.00 71 1.00 LysGln 264 258 0.89 (0.68–1.17) 0.41 162 0.90 (0.66–1.22) 0.48 96 0.88 (0.62–1.27) 0.51 GlnGln 94 85 0.82 (0.57–1.18) 0.28 55 0.87 (0.58–1.31) 0.51 30 0.76 (0.46–1.24) 0.27 LysGln + GlnGln 358 343 0.87 (0.68–1.13) 0.30 217 0.89 (0.67–1.89) 0.43 126 0.85 (0.60–1.20) 0.36 XPG Asn1104His AsnAsn 356 334 1.00 213 1.00 121 1.00 AsnHis 153 177 1.25 (0.96–1.63) 0.10 113 1.26 (0.93–1.70) 0.13 64 1.22 (0.85–1.75) 0.27 HisHis 23 21 0.99 (0.54–1.83) 0.98 9 0.69 (0.31–1.53) 0.36 12 1.50 (0.72–3.11) 0.28 AsnHis + HisHis 176 198 1.22 (0.94–1.57) 0.13 122 1.19 (0.89–1.59) 0.24 76 1.26 (0.89–1.77) 0.19 XPC Lys939Gln LysLys 189 171 1.00 105 1.00 66 1.00 LysGln 243 268 1.23 (0.94–1.61) 0.14 176 1.30 (0.96–1.78) 0.09 92 1.11 (0.76–1.60) 0.59 GlnGln 100 93 1.02 (0.72–1.45) 0.90 54 0.97 (0.64–1.46) 0.88 39 1.11 (0.70–1.77) 0.65 LysGln + GlnGln 343 361 1.17 (0.90–1.50) 0.23 230 1.21 (0.90–1.61) 0.21 131 1.11 (0.78–1.57) 0.56


150 B. Pardini et al. / Mutation Research 638 (2008) 146–153 T able 2 (Continued ) Genotypes Controls (n = 532) Cases (n = 532) OR (95% CI) p -V alue Colon (n = 335) OR (95% CI) p -V alue Rectum (n = 197) OR (95% CI) p -V alue Double-strand break repair XRCC3 Thr241Met ThrThr 219 203 1.00 133 1.00 70 1.00 ThrMet 250 264 1.14 (0.88–1.48) 0.32 162 1.07 (0.80–1.44) 0.65 102 1.27 (0.89–1.82) 0.18 MetMet 63 65 1.11 (0.75–1.65) 0.61 40 1.06 (0.67–1.66) 0.81 25 1.22 (0.71–2.09) 0.47 ThrMet + M etMet 313 329 1.13 (0.89–1.45) 0.32 202 1.07 (0.81–1.41) 0.64 127 1.26 (0.90–1.78) 0.18 NBS1 Glu185Gln GluGlu 239 246 1.00 154 1.00 92 1.00 GluGln 220 234 1.03 (0.80–1.33) 0.83 151 1.07 (0.80–1.43) 0.65 83 0.97 (0.68–1.38) 0.87 GlnGln 71 52 0.71 (0.48–1.06) 0.10 30 0.65 (0.40–1.04) 0.07 22 0.80 (0.47–1.38) 0.43 GluGln + GlnGln 291 286 0.95 (0.75–1.21) 0.68 181 0.97 (0.73–1.27) 0.81 105 0.93 (0.67–1.29) 0.67 The significant P v alues are gi v en in bold. a Adjusted for age and se x. OR, odds ratio; CI, 95% confidence interv al.

3.2. Interaction of genotypes with smoking habit and age

The modifying effect of smoking habit on associ-ation between DNA repair polymorphisms and CRC risk was evaluated by comparison of results for smokers and non-smokers. A significant interaction was observed between smoking habit and the hOGG1 Ser326Cys poly-morphism. Smokers with variant allele homozygous genotype for the polymorphism showed an increased risk of CRC (OR: 4.17; 95% CI: 1.17–15.54; p = 0.03).

Cases and controls were also stratified into three age groups of fairly similar size (tertiles of age distribution: 26–54, 55–63 and 64–86 years) and the associations with DNA repair polymorphisms were analysed. The associa-tion of APE1 Asn148Glu polymorphism with increased CRC risk became more pronounced in the age group of 64–86 years (OR: 1.79; 95% CI: 1.04–3.07; p = 0.04 for heterozygous genotype, and OR: 2.57; 95% CI: 1.30–5.06; p = 0.007 for homozygous genotype). This association was particularly evident for colon cancer (OR: 1.86; 95% CI: 0.99–3.50; p = 0.05 for heterozygous genotype and OR: 3.02; 95% CI: 1.41–6.49; p = 0.005 for homozygous genotype). Association with rectal can-cer risk was recorded for XPG Asn1104His in the group of oldest individuals (64–86 years) with homozygous variant allele (OR: 9.52; 95% CI: 1.59–57.02; p = 0.01).

4. Discussion

Polymorphisms in critical genes can potentially alter the susceptibility to different cancers including CRC. In this study, we tested the hypothesis, whether SNPs in the genes encoding different DNA repair enzymes influence the risk of this cancer. The study population was drawn from the Czech Republic, a country with one of the high-est incidence rates for CRC and the highhigh-est incidence rate for rectal cancer.

The strengths of the present study are matched cases and controls (as age and sex represent factors introduc-ing substantial bias in association studies[23]); adequate size; representative character of the study population; finally inclusion of colonoscopically determined neg-ative individuals as controls. Though the selection of controls may not necessarily represent the general pop-ulation, it does ensure disease-free control individuals.

The data analysis showed that none of the polymor-phisms included in the study was associated with the risk modulation of CRC. However, homozygote carri-ers of variant allele of the Asn148Glu polymorphism in the BER APE1 gene were at statistically non-significant increased risk of the disease. The stratification of cases


B. Pardini et al. / Mutation Research 638 (2008) 146–153 151

Table 3

Selected SNP–SNP interaction for CRC risk: results of unconditional logistic regression analysisa

APE1 Asn148Glu genotypes

Asn/Asn Asn/Glu Glu/Glu

hOGG1 Ser326Cys genotypes

Ser/Ser 97/92 [1] 164/169 [0.93 (0.65–1.32)] 75/69 [1.03 (0.67–1.59)]

Ser/Cys 40/59 [0.64 (0.39–1.04)] 86/86 [0.94 (0.62–1.43)] 42/35 [1.16 (0.68–1.97)] Cys/Cys 3/6 [0.50 (0.12–2.06)] 12/12 [0.99 (0.42–2.31)] 13/2 [6.37 (1.40–29.02)*] Values are represented as cases/controls [OR (95% CI)].

a Adjusted for age and sex. OR, odds ratio; CI, 95% confidence interval. * p = 0.02.

according to cancer site pointed to the effect of the 148Glu homozygous genotype confined to colon cancer. Interestingly, an observed increased risk in individuals, homozygous for variant alleles of the APE1 Asn148Glu and hOGG1 Ser326Cys polymorphisms in both CRC and colon cancer indicated multiplicative gene–gene interaction. This interaction between genes involved in BER is probably suggestive of a role for inflammatory processes and oxidative stress in the colon cancer. The APE1 and hOGG1 genes are known to repair oxida-tive DNA damage as a part of BER pathway[17]. The relationships between polymorphisms of these genes and functional outcomes have recently been highlighted in healthy subjects [13], showing that variant alleles of both polymorphisms were associated with signifi-cantly lower BER rates. Similar to our findings, the Ser326Cys polymorphism of hOGG1 was the only one (out of 12 investigated polymorphisms in BER genes) that showed a significant association with an increased risk of CRC in a Spanish population of CRC patients

[24]. Although hOGG1 Ser326Cys is one of the most frequently analysed BER polymorphisms, the outcomes remain inconclusive[25,26]. On the other hand, there is only one report on APE1 polymorphism on the CRC risk, where no significant association was found[24]. In general, none of the SNPs in any of the DNA repair genes have been so far significantly and repeatedly asso-ciated with adenoma or CRC risk[24,27–29]. However, the outcomes of different studies vary substantially (as reviewed recently in [19]). Our present results are in accordance with these observations that none of the individually analysed polymorphisms has been unam-biguously associated with CRC risk. Considering the putative subtle effect of many DNA repair polymor-phisms, the impact of individual SNPs on CRC risk is indeed expected to be low. Current assumption is that the onset of sporadic CRC may be triggered by multiple environmental/lifestyle factors with possible interaction with genetic factors like polymorphisms[4].

In the present study we attempted to address a major environmental/lifestyle factor, smoking and one major confounder, age. However, to include other variables would have decreased the statistical power, yielding unreliable outcome. We found a significant interaction between smoking habit and hOGG1 Ser326Cys poly-morphism. The smokers carrying 326Cys/Cys genotype showed an increased risk of CRC as compared to con-trol smokers. In another association study, based on 772 high-risk adenomas cases and 777 controls, a particular combination of three linked nonsynonymous polymor-phisms in XPC (Arg492His, Ala499Val, and Lys939Gln) increased smoking related risk for colorectal adenoma


Age also seems to be a relevant factor affecting the association between APE1 Asn148Glu polymorphism and an increased CRC risk, as the effect of above poly-morphism was more pronounced in individuals between 64 and 86 years old. The XPG Asn1104His polymor-phism exhibited an association with rectal cancer risk in the group of older individuals included in the study. Based on the current knowledge, this phenomenon is difficult to explain, however, many influencing factors can cause increased susceptibility during the lifetime. Another unsubstantiated explanation could be differ-ential accumulation of DNA damage due to different genotypes. This is likely to increase with increasing age due to diminished repair efficiency, which could be influenced by adverse genotypes in the repair genes. Similarly, Jin et al. [31] found that XRCC3 241Met allele was associated with CRC risk among older indi-viduals (>60 years). On the other hand, several studies reported increased susceptibility to adenoma or CRC risk in younger individuals[24,27,29]. Larger and well-designed studies are needed to address the role of DNA repair polymorphisms and ageing in CRC risk.

In the present study most of the associations observed between the cancer risk and various genotypes were marginal. However, in view of a strong hypothesis for the


152 B. Pardini et al. / Mutation Research 638 (2008) 146–153

role of DNA repair in CRC and an adequate and homoge-nous population investigated, these observations merit further investigation in larger populations. For many of the studied DNA repair polymorphisms the relationship with phenotypic outcome has recently been reported

[13,22], however, the link between the DNA repair genotype and phenotype is not fully understood. The complex etiology of CRC and the observed high inci-dence in the Czech Republic emphasize the importance of a systematic approach by combining epidemiologi-cal and molecular biologiepidemiologi-cal methods on large cohorts, in order to understand critical pathways in colorectal carcinogenesis. At the same time, several other factors contributing to CRC, such as microbial flora, inflam-matory processes, stool composition, etc., have to be simultaneously addressed.


The study was supported by grants GACR 310/05/2626, IGA MZ NR8563-5/2005, EU Diephy FOOD-CT-2003-505609, and by AVOZ 50390512. Bar-bara Pardini was a recipient of a fellowship for PhD studies from the Department of Biology, University of Pisa, Italy. Veronika Polakova was receiving PhD fellow-ship from the Third Medical Faculty, Charles University, Prague, Czech Republic.


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