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Polymorphisms in Genes of Nucleotide and Base Excision Repair: Risk and Prognosis of Colorectal Cancer

Authors' Affiliations: ¹ Institut d'Investigació Biomèdica de Bellvitge, Institut Catala d'Oncologia, Hospitalet; ² Laboratori de Bioestadistica Epidemiologia, Facultat de Medicina, Universitat Autonoma de Barcelona, Barcelona, Spain; ³ IARC, Lyon, France; and ⁴ Genetica, Dipartimento Scienze Uomo Ambiente, University of Pisa, Pisa, Italy

Requests for reprints: Federico Canzian, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, D-69120 Germany. Phone: 49-6221-421-791; Fax: 49-6221-421-810; E-mail: f.canzian{at}dkfz.de.

	Abstract

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Objectives: We have undertaken a comprehensive study of common polymorphisms in genes of DNA repair, exploring both the risk of developing colorectal cancer and the prognosis of patients.

Methods: Subjects from a case-control study (377 cases and 329 controls) designed to assess gene-environment interactions were genotyped by use of an oligonucleotide microarray and the arrayed primer extension technique. Twenty-eight single nucleotide polymorphisms in 15 DNA repair genes were included. The candidate genes belong to different DNA repair pathways: base excision repair (OGG1, LIG3, APEX, POLB, XRCC1, PCNA, and MUTYH), nucleotide excision repair (ERCC1, ERCC2, ERCC4, and ERCC5), double-strand breaks repair (XRCC2, XRCC3, and XRCC9), and reversion repair (MGMT) genes.

Results: Polymorphism OGG1 S326C was associated with an increased risk of colorectal cancer [odds ratio (OR), 2.3; 95% confidence interval (95% CI), 1.1-5.0], the risk being higher in younger individuals. A haplotype of ERCC1 was associated with increased risk (OR, 2.3; 95% CI, 1.0-5.3). POLB P242R was also associated with decreased risk (OR, 0.23; 95% CI, 0.05-0.99), although the number of variant allele carriers was low. In the univariate analysis, adjusted for age, sex, and Dukes' stage, three polymorphisms were significantly associated with better prognosis: XRCC1 R399Q [hazard ratio (HR), 0.38; 95% CI, 0.17-0.85], XRCC3 T141M (HR, 0.66; 95% CI, 0.45-0.97), and MGMT L84F (HR, 0.14; 95% CI, 0.02-0.99). ERCC1 19007T>C was associated with worse prognosis (HR, 1.51; 95% CI, 1.01-2.27). In a multivariate analysis, only XRCC1 R399Q and ERCC1 19007T>C remained significant. These associations were stronger among patients receiving adjuvant chemotherapy.

Conclusions: Although the overall effect of DNA repair genes in colorectal cancer etiology seems limited, their influence in the response to chemotherapy and prognosis may be more relevant. This knowledge may help to clarify the utility of specific adjuvant treatments according to the individual genetic background.

Although a defective mismatch repair is known to cause hereditary nonpolyposis colon cancer (3), much less is known about NER, BER, and DSBR pathways in the etiology of colorectal cancer. The investigation on the role of NER, BER, and DSBR genes on the risk of colorectal cancer started in relatively recent times. Some epidemiologic studies on polymorphisms within these genes and cancer reported both positive associations or lack of association. An overall evaluation of these studies suggests that the effect of common variants within NER, BER, or DSBR pathways on risk of colorectal cancer or adenoma is weak (4–14). No increase of colorectal cancer risk among carriers of germ line mutations of NER/DSBR genes, such as xeroderma pigmentosum genes, BRCA1, and BRCA2, has ever been reported. A recent study found a slightly increased colorectal cancer risk for carriers of mutations within ATM (13). For BER, a recent report showed an association with rare variants of MUTYH in homozygosis (12).

On the other hand, the role of NER, BER, and DSBR could be more relevant in affecting the response to chemotherapy. In fact, adjuvant chemotherapy causes an acute increase of DNA damage, and it is conceivable that alterations of DNA repair might be important under this type of cellular stress. Genetic polymorphisms within NER, BER, and DSBR genes could affect the response to chemotherapy and, ultimately, the overall survival of the patients. The finding that polymorphisms within DNA repair genes ERCC1 (codon 118), ERCC2 L751Q, and XRCC1 R399Q could alter the overall survival and time to progression of colorectal cancer, in patients who receive 5-fluorouracil (5-FU) and oxaliplatin, reinforces this notion (15–17). Interestingly, ERCC2 and XRCC1 confirmed their prognostic role in patients with non–small cell lung cancer receiving platinum chemotherapy (18).

Here, we report a case-control association study of colorectal cancer, where a comprehensive analysis of single nucleotide polymorphisms (SNP) within multiple genes of the DNA repair was done. We employed a microarray platform allowing the simultaneous genotyping of 28 SNPs within 15 genes of the BER (OGG1, LIG3, APEX, POLB, XRCC1, PCNA, and MUTYH), NER (ERCC1, ERCC2, ERCC4, and ERCC5), DSBR (XRCC2, XRCC3, and XRCC9), and reverse repair (MGMT) pathways. We studied the association of these polymorphisms with susceptibility to the disease and explored the prognostic value of these polymorphisms, by studying the survival rates in patients who underwent chemotherapy and were followed up for a median time span of 72 months.

	Materials and Methods

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Study population. Cases were patients with a new diagnosis of colorectal adenocarcinoma attending a University Hospital in Barcelona, Spain between January 1996 and December 1998. A detailed description of the study population, composition, and interviews has been given elsewhere (19). In brief, this study includes those 377 (72% of eligible) who could be interviewed and who provided biological samples of sufficient quality for genetic analysis. Refusals were 2% of eligible, whereas 14% could not be interviewed because they either had died, had mental or some other impairment, or were released without being approached and could not be traced. Finally, 12% were interviewed but did not provide biological samples. These lost cases were similar to those included with respect to age, sex, tumor location, and stage. The controls (n = 329, 69.4% of eligible) were people randomly enrolled among patients admitted to the same hospital during the same period of time. Refusals were 7% of eligible, whereas 5% could not be interviewed because of mental or other impairment. Finally, 18.6% were interviewed but did not provide a blood sample. To avoid selection bias, the criterion for inclusion of controls was that the reason for the current admittance to the hospital should be a new disease (not previously diagnosed) for that patient. This criterion was used to avoid inclusion of patients with chronic diseases, who might be repeatedly admitted to hospital and modify their habits because of their disease. This criterion of enrollment paralleled those of the cases. The Ethic Committee of the hospital cleared the study protocol, and all individuals gave written informed consent to participate and for genetic analysis to be done on their samples.

Distribution of cases was about one third in each of the sites (rectum, right colon, and left colon). The distribution of cases by Dukes' stage was A (7%), B (42%), C (32%), and D (19%). Adjuvant chemotherapy was given to 166 (44%) of the cases (36% of stage B, 63% of stage C, and 41% of stage D). Among them, 66 (18%) patients of rectal cancer also received radiotherapy. In the standard treatment protocol of the hospital, after surgery, patients fulfilling criteria received 5-FU-based adjuvant chemotherapy. In the first 2 years of the study 5-FU/levamisole (5-FU, 450 mg/m² bolus injection on days 1-5 and after 4 weeks once a week plus levamisole, 50 mg thrice a day (oral) on days 1-3 and 15-17 for 1 year) was the standard treatment. From 1998 onwards, 5-FU/leucovorin (5-FU, 425 mg/m² bolus injection on days 1-5 and leucovorin, 20 mg/m² i.v. on days 1-5 every 28 days for 6 months) was given. Cases were actively followed up from diagnosis to November 2004. Median follow-up time was 72 months, and in this period, 121 (32%) deaths were observed.

SNP selection and genotyping. We selected candidate polymorphisms within genes described in previous studies (also referring to other cancer sites). In addition, we included polymorphisms discovered recently and published in publicly available databases, such as the SNP500 Cancer Project (http://snp500cancer.nci.nih.gov) and dbSNP (http://www.ncbi.nlm.nih.gov/SNP). To have a sufficiently high statistical power, we included only SNPs with minor allele frequency of >1%. However, we included some polymorphisms for which the frequency was not previously known (taking the risk to include rare variants) but that had reasonable chances to alter the function of the gene, such as missense variants.

Genotyping of all SNPs was done simultaneously (except MUTYH) using a microarray based on arrayed primer extension (APEX) technology as described previously (20, 21). APEX consists of a sequencing reaction primed by an oligonucleotide anchored with its 5' end to a glass slide and terminating just one nucleotide before the polymorphic site. A DNA polymerase extends the oligonucleotide by adding one fluorescently labeled dideoxynucleotide triphosphate complementary to the variant base. Reading the incorporated fluorescence identifies the base in the target sequence. This method is suitable not only for SNPs but also for small insertion/deletion polymorphisms. Because both sense and antisense strands are sequenced, two oligonucleotides were designed for each polymorphism. In general, two 30-mers, one for each strand, complementary to each side of the polymorphism were designed both with their 3' pointing towards the polymorphism. The flanking sequences and their related APEX-oligonucleotides are available from the authors upon request. Five-prime (C-12) amino linker oligonucleotides were synthesized by Sigma Genosys (Sigma-Genosys Ltd., Cambridge, United Kingdom) and spotted onto silanized slides. PCR products were pooled, purified, concentrated using Millipore Microcon MY30 columns, and fragmented as reported in detail elsewhere (19). Genomic DNA was amplified to enrich the fragments carrying the SNPs by using specific primer pairs. For single-base extension reaction, fragmented PCR products were incubated onto the slides together with the fluorescently labeled dideoxynucleotide triphosphates (4 x 50 pmol), 10x buffer, and 4 units of Thermo Sequenase (Amersham Biosciences, Piscataway, NJ). Slides were imaged by a Genorama-003 four-color detector equipped with Genorama image analysis software (Asper Biotech, Tartu, Estonia). Fluorescence intensities at each position were converted automatically into base calls by the software, under the supervision of an operator. In case of more than one signal present on a given position, only the main signal was considered, when the intensity of the weaker signal was <10% of the main signal. MUTYH was genotyped by means of fluorescent hybridization probe melting curves using the Light Cycler instrument.

Quality control of genotyping. Quality control of genotyping was insured by different strategies:

• Each APEX oligonucleotide was spotted in duplicate. This allowed to detect and exclude false-positive signals.
  
• Each SNP was analyzed independently by genotyping both the sense and the antisense strand. Genotyping calls were not considered when sense signal was not consistent with the antisense signal.
  
• APEX microarray was equipped of internal controls allowing to check the correct incorporation of the four fluorescently labeled terminators.
  
• Two trained operators reviewed independently the performance of the genotyping software by visual inspection of each spot.
  
• Five percent of the samples, randomly selected and recoded, were repeated blindly, allowing to check if sample processing has been done correctly.
  
• DNA samples with known genotype from the SNP500cancer project (http://snp500cancer.nci.nih.gov) were run blindly on the same microarray platform to verify the goodness of genotyping.
  

Statistical analysis and haplotype reconstruction. Each polymorphism was tested in controls to ensure the fitting with Hardy-Weinberg equilibrium. To test the hypothesis of association between genetic polymorphisms and colorectal cancer, multivariate methods based on logistic regression analyses were used. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for each genotype compared with the homozygous for the major allele (the allele with greater frequency among controls), which were set as the reference genotype.

Analyses were initially done under a codominant inheritance model (three genotypes separated). Then, simplified models were fitted: a dominant model (heterozygous grouped with the homozygous for the minor allele), a recessive model (heterozygous grouped with the homozygous for the major allele), and an additive model (a score was assigned counting the number of minor alleles: the homozygote for the major allele was given score 0, the heterozygote score 1, and the homozygote for the minor allele score 2). The model with lowest Akaike information criteria (minus twice the log likelihood of the model plus the number of variables in the model) was selected for an easy summary of the results. All analyses were adjusted for age and sex because the design of the study was frequency matched by these variables. Other risk factors for colorectal cancer (family history, alcohol and energy intake, nonsteroid anti-inflammatory drug use, and body mass index) were excluded as confounders because they were independent of the studied genotypes. Ps were derived from likelihood ratio tests, and a significance level of 5% (two sided) was used for the analyses. Tests for interaction between polymorphisms and age were done. For these analyses, age was categorized using cut points 55 and 70. This resulted in groups of unequal sample size, but the cut point selection aimed to differentiate cases diagnosed at young ages (<55 years), which might be more related to genetic determinants, and cases at older ages (70 years), which might be more related to environmental determinants.

Haplotypes were reconstructed using the software PHASE (22), and a global test of hypothesis for the gene was carried out, followed by contrasts for specific haplotypes, assuming an additive model. Posterior probabilities for each compatible haplotype were used as weights in the model to account for uncertainty in the identification of phase unknown haplotypes. Analysis of the prognostic value of the polymorphisms was done using proportional hazards models adjusted for age, sex, and tumor stage. The Kaplan-Meier method was used for the estimation of survival probabilities.

Because we have explored many SNPs and used several inheritance models, some may show significant just by chance. An estimate of the probability of false discoveries has been calculated for significant results. This methodology is based on a Bayesian framework and requires providing a subjective estimate of the prior probability that a result is really positive. This prior, combined with the P observed in the study, determines the posterior probability that is called the false-positive result probability (FPRP; ref. 23).

	Results

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The main characteristics of the population under study have been shown elsewhere (19). Positive familial history of colon cancer, high energy intake, and alcohol consumption were associated with increased risk of colorectal cancer in this population, whereas use of nonsteroid anti-inflammatory drugs was associated with a reduced risk of colorectal cancer.

The frequencies of the genotypes for each polymorphism studied are shown in Table 1 . The frequencies are in agreement with previous reports and are in Hardy-Weinberg equilibrium among controls. Genotyping failures occurred randomly across all SNPs, with a median completion rate of 95.6% (range, 70.5-97.3%). Table 1 also shows the association analyses of each polymorphism in relation to colorectal cancer for the codominant model of inheritance. Significant associations have been found for genes OGG1 and POLB belonging to the BER pathway. Homozygous carriers of the OGG1 S326C polymorphism had a significantly increased risk of colorectal cancer compared with carriers for the major allele (for the recessive model that combines as reference group individuals homozygous for the major allele and heterozygous: OR, 2.31; 95% CI, 1.05-5.09; P = 0.031). Polymorphism POLB P242R was significantly associated with a reduced risk of colorectal cancer (OR, 0.23; 95% CI, 0.05-0.99; P = 0.038), although the minor allele is very rare, and only a few heterozygous individuals were observed.

Interactions with age. Because there are previous reports that the associations of some DNA repair polymorphisms are restricted to individuals with younger age (4, 11), we explored the interactions with age (Table 2 ). A significant interaction was observed for OGG1 S326C (P = 0.01). The risk of colorectal cancer associated to the Cys/Cys genotype was higher for individuals of younger age. Similarly, XRCC1 R194W and R280H but not R399Q showed a significant interaction with age (P = 0.04, 0.05, and 0.32, respectively). For both polymorphisms of XRCC1, the minor allele was associated with a decreased risk of colorectal cancer among individuals aged 54 years when compared with those aged 70 years.

View larger version (9K): [in this window] [in a new window]   Fig. 1. Survival curves for XRCC1 R399Q genotypes. Kaplan-Meyer survival curves for the Arg to Gln polymorphism at codon 399 within XRCC1 gene. The homozygotes for the glutamine variant show a better overall survival (P for the additive model = 0.004) than the carriers for Arg allele.

	Discussion

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Among BER gene polymorphisms, only the S326C variant of OGG1 was convincingly associated to a moderately increased risk of colorectal cancer. Interestingly, the OGG1 S326C polymorphism was shown to decrease repair ability (24). OGG1 polymorphisms have been previously associated with increased risk of lung, esophagus, and prostate cancer (25). One study reported a negative result for the S326C SNP and colorectal cancer (6), although an interaction in relation to the risk of high meat consumption was reported. We have not been able to confirm this interaction in our study. However, we have observed that the increase in risk is higher among cases detected in younger ages, which is in agreement with a genetic predisposition to the disease. Interestingly, OGG1 and MUTYH function in consort to identify and repair 8-hydroxyguanine incorporated into DNA, as well as to remove modified nucleoside, and a recent study reported that homozygosity for rare variants of MUTYH confers a strong increase in risk for colorectal cancer (12). In our study, however, these variants of MUTYH were not related to colorectal cancer, and we did not find any homozygous individual, due to limited sample size. Recently, a decreased risk for carriers of OGG1 S326C has been reported for colorectal carcinomas but not for adenomas (14). These mixed results may be related to random variation because the sample sizes used in all studies are relatively small.

Several variants in XRCC1 have been studied in relation to cancer, although with mixed results. Variant R194W tends to be associated with decreased risk of cancer (25, 26), whereas R280H and R399Q, when associated, tend to increase the risk. In relation to colorectal cancer, similar results have been reported both for R194W and R399Q (4, 7, 9, 11). Here, we have found a nonsignificant decreased risk for the R280H variant and no overall effect for the others. However, a decreased risk for R194W and R280H was stronger and significant among younger patients, although the test for interaction was not strongly significant (P = 0.04). The mixed results when compared with other studies in colon and other cancers suggest that this observation might be a chance finding.

Overall, the polymorphisms studied in genes involved in NER and DSBs were not associated to colorectal cancer. ERCC1 17677A>C approached statistical significance, and one haplotype that includes its minor allele and other two minor alleles of polymorphisms located in exon 4 and intron 6 is associated with increased risk of colorectal cancer. The SNP in exon 4 has previously been studied in relation to colorectal cancer with negative results (8). More studies will be needed to clarify the role of ERCC1 in determining the risk of colorectal cancer, especially considering the fact that in our study variants of this gene were also associated with a reduced survival among patients followed up.

The variants studied in the other genes were unrelated to colorectal cancer, in this study. Our results are in agreement with the studies published thus far on these genes. A study reported a lack of association for ERCC1, ERCC2, ERCC4, ERCC5, and XRCC1 and a slight increased risk for XRCC3 (8). Moreover, variants XRCC3 T241M (9–11) and ERCC2 (XPD) L751Q (11) have been studied in relation to colorectal cancer with negative results similar to ours.

We have found three genes (XRCC1, XRCC3, and MGMT) with variants significantly associated with better prognosis and one variant in ERCC1 associated with worse prognosis. This result is in agreement with the possibility that defective DNA repair enhances the likelihood that the tumor responds to adjuvant chemotherapy. This hypothesis is corroborated by the fact that SNP XRCC1 R399Q was significantly associated with improved prognosis in patients who received chemotherapy but not in those who received surgery alone. There is one previous report that XRCC1 R399Q could be related to worse prognosis in advanced colorectal cancer treated with 5-FU/oxaliplatin (15), although the same authors subsequently reported no association in a larger group of patients (17). In that situation, the authors argued that tumor cells could develop resistance to chemotherapy. This potential mechanism could be active in advanced tumors, which tend to be more genetically unstable, or could be specific to oxaliplatin. Patients with lung cancer treated with platinum also had worse prognosis related to variant alleles in XRCC1 and ERCC2 (XPD; ref. 18). In our series, most of tumors were diagnosed in Dukes' stages B and C, with only 19% at stage D. We did not find a differential effect in this latter group of patients, who where essentially treated with 5-FU/leucovorin. This is an unselected consecutive series of cases and represents the usual stage distribution at diagnosis observed in Spain. For less-advanced tumors, we believe that enhanced sensitivity to chemotherapy is a plausible mechanism to explain the observed results. The confirmation of our results may have a relevant clinical implication because colorectal cancer is considered to be relatively resistant to chemotherapy, and knowledge of the status of a series of genes that confer sensitivity might help in selecting the treatments more accurately.

We are aware that this study has some limitations. The sample size is limited to detect associations when the variant alleles are rare, or to detect interactions with exposures susceptible to cause DNA damage. Although the control series is hospital based, we believe that genes of DNA repair should not affect the likelihood of an individual to be hospitalized, although this cannot be completely excluded and could contribute to find negative results.

This study has tested many hypothesis and, although only a few have shown a significant result, these might have appeared just by chance. The calculation of the FPRP may be a useful way tool to assess the noteworthiness of the findings. In our results, for OGG1 S326C there are previous functional studies reporting DNA repair deficiency for this variant, and this variant has been associated with increased risk in other tumors. We believe that the prior probability of association with colorectal cancer could be in the range of 1% to 10%, which results in a FPRP below 50%, which is considered the threshold of noteworthiness. Similar conclusions can be derived from the FPRP calculations for the assessment of the prognosis value found for XRCC1 R399Q and MGMT L84F. The FPRP is much higher for other significant results with Ps > 0.01, or when the prior information about functionality or implication in other tumors is absent, like POLB P242R.

In conclusion, common variants in DNA repair genes belonging to BER, NER, and DSBR seem to be largely unrelated to the etiology of sporadic colorectal cancer, although we have found a significantly increased risk for OGG1 S326C. These observations parallel the lack of involvement of germ line mutations within NER and DSBR genes and a possible contribution of BER genes (12) to the etiology of colorectal cancer. Patients carrying variants in XRCC1, XRCC3, MGMT and a common allele of ERCC1 show better prognosis, which might be related to enhanced sensitivity to chemotherapy, and knowledge of this may help to clarify the utility of specific adjuvant treatments based on the individual's genotype in the future.

	Footnotes

 
Grant support: Marathon of TV3 grant 48/95; Fondo de Investigaciones Sanitarias grants FIS 96/0797, FIS 00/0027, and FIS 03/114; Red de Centros de Epidemiología y Salud Pública grant C03/09; Red temática de investigación cooperativa de centros de cáncer grant C03/10; Comisión Interministerial de Ciencia y Tecnología grants SAF 2000/81 and SAF 2003/05821; and Association pour la Recherche sur le Cancer grant 7478.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: V. Moreno, F. Gemignani, and S. Landi, contributed equally to this work.

F. Gemignani is a recipient of a fellowship of the International Association for the Study on Lung Cancer, part of the Cancer Research Foundation of America. S. Landi is a recipient of a Marie Curie fellowship grant HPMFCT-2000-00483 of the European Commission.

F. Canzian is currently at the German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, D-69120 Germany.

The members of the Bellvitge Colorectal Cancer Study Group are Victor Moreno, Matilde Navarro, Joan Marti-Ragué, Javier de Oca, Alfonso Osorio, Carlos del Rio, Sebastiano Biondo, Maria Cambray, Josep M. Badosa, Felip Vilardell, Belen Lloveras, Elisabet Guino, Sara González, Mireia Menéndez, Miguel A. Peinado, and Gabriel Capellà. Addresses: IARC, 150 Cours Albert Thomas 69372, Lyon 08, France; Genetica, Dip. Scienze Uomo Ambiente, Via S. Giuseppe 22, 56100 University of Pisa, Pisa, Italy; Institut Catala d'Oncologia, Gran Via km 2.7, 08907, Hospitalet, Barcelona, Spain.

Received 6/22/05; revised 1/11/06; accepted 1/17/06.

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