Identification of single nucleotide polymorphisms in human DNA repair genes

Variation in gene coding sequence represents a significant factor in predisposition to disease, including cancer. Variants of some DNA repair genes (e.g. MLH1, MSH2 and MSH6) are known to predispose to cancer. We identified single nucleotide polymorphisms (SNPs) in five DNA repair genes in 142 healthy individuals using a DNA sequencing protocol optimized for the direct detection of single nucleotide polymorphisms. This approach, called the heterozygote sequencing protocol (HSP), enables moderate-scale population surveys of SNPs. HSP uses fluorescently tagged primers and exploits the large dynamic range and low background of automated fluorescent sequencing. HSP may be used for any sequence that can be amplified by PCR. A total of 12 SNP variants in MGMT, ERCC1, CDK7, CCNH and XRCC4 were identified, 11 at polymorphic frequencies, with an average frequency of 0.22 (95% confidence interval 0.20-0.24). Among the 82 individuals for whom complete SNP profiles were available, no one person carried the GenBank reference sequence for all five genes. The extensive heterogeneity observed in these five genes is intriguing. All variants are in Hardy-Weinberg equilibrium, although the meaning of this equilibrium is unclear. Using this approach, possible associations of sequence variation, and hence of variation in DNA repair, with disease risk can be assessed.     

碱基切除修复基因单核苷酸多态性和晚期非小细胞肺癌治疗疗效研究

  目的 探讨碱基切除修复交叉互补基因（XRCC1）和脱嘌呤／脱嘧啶核酸内切酶（APE1）单核苷酸多态性与非小细胞肺癌（NSCLC）放化疗疗效的关系。方法 230例晚期不能手术治疗的NSCLC患者为试验对象。取患者治疗前抗凝外周血，提取有核细胞DNA，采用Taqman探针基因分型技术检测XRCC1 Arg194Trp，XRCC1 Arg399Gln 和APE1 Asn148Glu单核苷酸多态性。结果 在单纯化疗或放疗的患者中，治疗敏感和不敏感的患者XRCC1、 APE1基因型差异无统计学意义。在放化疗联合治疗组中，XRCC1基因型与疗效无显著性相关，但APE1（Asn148Glu，T／G）位点与疗效有一定的相关性。在Ⅲa和 Ⅲb无胸膜浸润组，携带有G／G或G／T基因型的患者对放化疗不敏感的可能性是携带有T／T基因型患者3.25倍（P = 0.043）。结论 APE1 Asn148Glu位点可能是一个依赖于临床分期的放化疗疗效预测的指标，APE1野生纯合型148 T／T（Asn148Asn）可能是Ⅲa期和Ⅲb期无胸膜浸润NSCLC放化疗敏感的标志。     

Genetic polymorphisms of the XPG and XPD nucleotide excision repair genes in sarcoma patients

There are more than 50 subtypes of soft tissue sarcomas, among which 30% are associated with specific genetic alterations, including translocations. Several studies have reported associations between cancer risk and polymorphisms of DNA repair genes from the nucleotide excision repair (NER) pathway. NER involves more than 20 proteins whose inactivation leads to xeroderma pigmentosum (XP) or cockayne syndrome (CS), among which XPD, a helicase allowing DNA strand excision by the endonuclease XPG. DNA from 93 patients with synovial sarcomas, myxoid liposarcomas, dermatofibrosarcomas protuberans (DFSP), malignant fibrous histiocytomas and leiomyosarcomas were genotyped for both XPD Lys751Gln and XPG Asp1104His polymorphisms. Departure from Hardy-Weinberg was highly significant for the XPG polymorphism with an excess of heterozygotes in synovial sarcomas (p = 1.5 x 10(-5)), myxoid liposarcomas (p = 1.5 x 10(-4)) and to a lesser extent in DFSP (p = 0.028). In the case of XPD, a significant deviation was observed in synovial sarcomas (p = 3 x 10(-6)) and DFSP (p = 0.0014). When tumors were pooled according to their genetic alterations, the proportion of carriers of the variant XPG allele was significantly increased in sarcomas with specific translocations as compared to sarcomas with complex genetics (p < 10(-9)). No difference was found for XPD. Genotyping of the tumor samples in synovial sarcomas and myxoid liposarcomas revealed frequent loss of heterozygosity for XPG, mostly due to the loss of the frequent allele. For XPD, both alleles were lost with a similar frequency. Our results raise the potential implication of the XPG Asp1104His polymorphism in the occurrence of chromosomal translocations associated with specific subtypes of sarcomas.     

Potentially functional single nucleotide polymorphisms in the core nucleotide excision repair genes and risk of squamous cell carcinoma of the head and neck.

Susceptibility to cancer has been associated with DNA repair capacity, a global reflection of all functional variants, most of which are relatively rare. Among the 1,098 single nucleotide polymorphisms (SNP) identified in the eight core nucleotide excision repair genes, only a few are common nonsynonymous or regulatory SNPs that are potentially functional. We tested the hypothesis that seven selected common nonsynonymous and regulatory variants in the nucleotide excision repair core genes are associated with risk of squamous cell carcinoma of the head and neck (SCCHN) in a hospital-based, case-control study of 829 SCCHN cases and 854 cancer-free controls. Assuming a recessive genetic model, we found that only carriers of the XPC 499Val/Val genotype had a significantly increased SCCHN risk (adjusted odds ratio, 1.65; 95% confidence interval, 1.16-2.36). In analysis of the joint effects, the number of observed risk genotypes was associated with SCCHN risk in a dose-response manner (P for trend = 0.017) and those who carried four or more risk genotypes exhibited a borderline significant 1.23-fold increased SCCHN risk (adjusted odds ratio, 1.23; 95% confidence interval, 0.99-1.53). In the stratified analysis, the dichotomized combined effect of the seven SNPs was slightly more evident among older subjects, women, and laryngeal cancer. These findings suggest that these potentially functional SNPs may collectively contribute to susceptibility to SCCHN. These findings need to be validated in larger, independent studies.     

Susceptibility to arsenic-induced skin lesions from polymorphisms in base excision repair genes

Genetic polymorphisms in the base excision DNA repair pathway may influence individual susceptibility to arsenic and the development of arsenic-induced skin lesions. Data from a case-control study of 792 cases and 792 matched controls conducted in Bangladesh from 2001 to 2003 were analyzed using conditional logistic regression to assess the associations between four common base excision repair (BER) genetic polymorphisms X-ray repair cross-complementing group 1 (XRCC1) Arg399Gln, XRCC1 Arg194Trp, human 8-oxoguanine DNA glycosylase (hOGG1) Ser326Cys and apurinic/apyrimidinic endonuclease (APE1) Asp148Glu and arsenic-induced skin lesions including melanosis and keratosis. Adjusted for toenail arsenic, body mass index, education, smoking and betel nut use, individuals with the APE1 148Glu/Glu polymorphism had a 2-fold increased odds of skin lesions compared with individuals with the 148Asp/Asp genotype (1.93; 95% confidence interval 1.15, 3.19). Gene-environment interactions between toenail arsenic and XRCC1 Arg194Trp and APE1 Asp148Glu were observed. Within the lowest arsenic tertile, APE1 148Glu/Glu had 2.5 times the odds ratio compared with wild-type, whereas within the highest tertile of arsenic the odds ratios for skin lesions did not differ. In contrast, at low arsenic levels, the odds ratios for skin lesions did not differ much by XRCC1 Arg194Trp genotype. However, at the highest tertile of arsenic, the XRCC1 194Arg/Arg polymorphism conferred a 3-fold larger odds ratio for skin lesions compared with XRCC1 194Trp/Trp. Individuals may have different odds for developing skin lesions based in part on their genetic profile for BER and their arsenic exposure history. Future research on arsenic-induced skin lesions should consider the impact of genetic variation to individual susceptibility to arsenic toxicity.     

Association of single nucleotide polymorphisms of nucleotide excision repair genes with laryngeal cancer risk and interaction with cigarette smoking and alcohol drinking

We investigated the potential association of 12 single nucleotide polymorphisms (SNPs) of nucleotide excision repair (NER) genes with risk of laryngeal cancer. A ratio of 1:1 matched case–control study was conducted. Conditional regression analysis indicated that subjects with ERCC1 rs11615 CC and C allele had an increased risk of laryngeal cancer compared with the TT genotype. Individuals with the ERCC5 rs17655 GG and G allele had a moderately increased risk of laryngeal cancer when compared with the CC genotype. By stratified analysis, ERCC1 rs11615 CC genotype and C allele were significantly associated with greatly increased risk of laryngeal cancer in ever smokers. ERCC1 rs11615 and ERCC5 rs17655 polymorphisms were associated with a moderately increased risk of this cancer in ever drinkers. In summary, we suggest that genetic variations in ERCC1 rs11615 and ERCC5 rs17655 are associated with laryngeal cancer risk in a Chinese population, especially in ever smokers and drinkers. Our finding could be helpful in identifying people at high risk for the disease for early intervention.     

DNA repair gene polymorphisms in the nucleotide excision repair pathway and lung cancer risk: A meta-analysis

Objective: A number of studies have reported the association of "XPA", "XPC", "XPD/ERCC2" gene polymorphisms with lung cancer risk. However, the results were conflict. To clarify the impact of polymorphisms of "XPA", "XPC", "XPD/ERCC2", on lung cancer risk, a meta-analysis was performed in this study. Methods: The electronic databases PubMed and Embase were retrieved for studies included in this meta-analysis by "XPA", "XPC", "XPD/ERCC2", "lung", "cancer/neoplasm/tumor/carcinoma", "polymorphism" (An upper date limit of October, 31, 2009). A meta-analysis was performed to evaluate the relationship among XPA, XPC and XPD polymorphism and lung cancer risks. Results: A total of 31 publications retrieved from Pubmed and Embase included in this study. XPC A939C CC genotype increased lung cancer risk in total population (recessive genetic model: OR=1.23, 95% CI:1.05-1.44; homozygote comparison: OR=1.21,95%CI:1.02-1.43and CC vs. CA contrast: OR=1.25,95%CI:1.06-1.48), except in Asians. XPD A751C, 751C allele and CC genotype also increased lung cancer risk in total population and in Caucasians (recessive genetic model: Total population: OR=1.20, 95%CI:1.07-1.35). No significant correlation was found between XPD A751C and lung cancer risk in Asians and African Americans. XPD G312A AA genotype increased lung cancer risk in total population, in Asians and Caucasians(recessive genetic model: Total population: OR=1.20, 95%CI: 1.06-1.36). No significant association was found between XPA G23A, XPC C499T, XPD C156A and lung cancer risk. Conclusion: Our results suggest that the polymorphisms in XPC and XPD involve in lung cancer risks. XPA polymorphisms is less related to lung cancer risk.     

Single nucleotide polymorphisms in nucleotide excision repair genes,cancer treatment,and head and neck cancer survival

Purpose

Head and neck cancers (HNC) are commonly treated with radiation and platinum-based chemotherapy, which produce bulky DNA adducts to eradicate cancerous cells. Because nucleotide excision repair (NER) enzymes remove adducts, variants in NER genes may be associated with survival among HNC cases both independently and jointly with treatment.

Methods

Cox proportional hazards models were used to estimate race-stratified (White, African American) hazard ratios (HRs) and 95 % confidence intervals for overall (OS) and disease-specific (DS) survival based on treatment (combinations of surgery, radiation, and chemotherapy) and 84 single nucleotide polymorphisms (SNPs) in 15 NER genes among 1,227 HNC cases from the Carolina Head and Neck Cancer Epidemiology Study.

Results

None of the NER variants evaluated were associated with survival at a Bonferroni-corrected alpha of 0.0006. However, rs3136038 [OS HR = 0.79 (0.65, 0.97), DS HR = 0.69 (0.51, 0.93)] and rs3136130 [OS HR = 0.78 (0.64, 0.96), DS HR = 0.68 (0.50, 0.92)] of ERCC4 and rs50871 [OS HR = 0.80 (0.64, 1.00), DS HR = 0.67 (0.48, 0.92)] of ERCC2 among Whites, and rs2607755 [OS HR = 0.62 (0.45, 0.86), DS HR = 0.51 (0.30, 0.86)] of XPC among African Americans were suggestively associated with survival at an uncorrected alpha of 0.05. Three SNP-treatment joint effects showed possible departures from additivity among Whites.

Conclusions

Our study, a large and extensive evaluation of SNPs in NER genes and HNC survival, identified mostly null associations, though a few variants were suggestively associated with survival and potentially interacted additively with treatment.     

DNA修复基因单核苷酸多态性与铂类药物抵抗研究进展

目前,肿瘤的标准化疗仍然是以解剖部位为基础选择化疗药物,但由于肿瘤本身以及患者个体之间异质性的存在,同一部位的肿瘤对标准化疗的敏感性及化疗产生的毒副反应差异很大。以肿瘤自身药物敏感性为指导开展个体化的药物治疗成为多年来临床研究的热点。随着人类基因组计划的完成,恶性肿瘤的分子亚分类成为可能,以药物敏感相关基因为检测目标的药物基因组学、药物遗传学获得快速发展,使个体化的药物治疗成为可能。     

Single nucleotide polymorphisms in DNA repair genes and basal cell carcinoma of skin

In addition to environmental exposures like UV radiation and, in some cases, arsenic contamination of drinking water, genetic factors may also influence the individual susceptibility to basal cell carcinoma of skin (BCC). In the present study, 529 cases diagnosed with BCC and 533 controls from Hungary, Romania and Slovakia were genotyped for one polymorphism in each of seven DNA repair genes. The variant allele for T241M (C>T) polymorphism in the XRCC3 gene was associated with a decreased cancer risk [odds ratio (OR), 0.73; 95% confidence interval (CI), 0.61-0.88; P = 0.0007, multiple testing corrected P = 0.004]. The risk of multiple BCC was significantly lower among variant allele carriers than in non-carriers (P = 0.04). Men homozygous for the C-allele for E185Q (G>C) polymorphism in the NBS1 gene showed an increased BCC risk (OR, 2.19; 95% CI, 1.23-3.91), but not women (OR, 0.84; 95% CI, 0.49-1.47). In men, the age and nationality adjusted OR for the genotype CC (XRCC3)/CC (NBS1) was 8.79 (95% CI, 2.10-36.8), compared with the genotype TT (XRCC3)/GG (NBS1). The data from this study show overall risk modulation of BCC by variant allele for T241M polymorphism in XRCC3 and gender-specific effect by E185Q polymorphism in NBS1.     

Nonsynonymous single nucleotide polymorphisms in DNA damage repair pathways and lung cancer risk

BACKGROUND:

Several reports have revealed the association between single nucleotide polymorphisms (SNPs) and the development of cancer. Although many SNPs have been investigated, they were tested individually. In this study, nonsynonymous SNPs present in DNA damage response genes were comprehensively analyzed for lung cancer susceptibility.

METHODS:

The authors selected 37 nonsynonymous SNPs in 23 genes involved in DNA damage repair pathways. Fifty lung adenocarcinoma patients resected at their institution between 2002 and 2005 and 50 individuals without any known history of cancer were recruited for a case‐control study.

RESULTS:

Three variants (XRCC1 194Trp homozygotes, POLδ1 119His homozygotes, and RAD9 239Arg heterozygotes) tended to coassociate with lung cancer risk. The authors analyzed and calculated whether the association between combinations of these 3 SNPs significantly affected the risk of lung cancer. Compared with carriers of either XRCC1 194Trp homozygote or RAD9 239Arg heterozygote variants, noncarriers were at a significantly decreased risk for lung cancer (odds ratio [OR], 0.282; confidence interval [CI], 0.089‐0.893). The same results were found for the combination of POLδ1 119His homozygotes and RAD9 239Arg heterozygotes (OR, 0.277; CI, 0.077‐0.993). Moreover, compared with carriers that had at least 1 of the 3 variants, noncarriers showed a more significant decrease in risk (OR, 0.263; CI, 0.090‐0.767).

CONCLUSIONS:

Analysis of the presence of XRCC1 194Trp homozygote, POLδ1 119His homozygote, and RAD9 239Arg heterozygote variants revealed that their coassociation leads to a significant risk for the development of lung adenocarcinoma. Inclusive analyses of different SNPs were important in this cancer risk study. Cancer 2010. © 2010 American Cancer Society.     

Expression of base excision DNA repair genes as a biomarker of oxidative DNA damage

Oxidative stress induced DNA damage is considered to be the most common insult affecting the genome. Moreover, it is recognized as a common pathway to mutations and is suggested to play a major role in the development of chronic diseases such as cancer. However, current analytical methods used to detect oxidative DNA damage have been hampered by both technical and biological obstacles. These include spurious oxidation during DNA isolation and processing, and the inherent removal of damaged bases by numerous operating DNA repair systems. The removal of oxidized bases is performed predominantly by the base excision repair (BER) pathway and it has been shown that induction of DNA repair genes occurs in response to oxidative stress. Here, we demonstrate the utility of measuring changes in expression of BER genes as a sensitive in vivo biomarker for oxidative DNA damage.     

Association between polymorphisms in DNA base excision repair genes XRCC1, APE1, and ADPRT and differentiated thyroid carcinoma

PURPOSE: DNA BER pathway is related with carcinogenesis. We hypothesized that functional polymorphisms of three BER genes, XRCC1, apurinic/apyrimidinic endonuclease (APE1), and ADPRT, confer risks for DTC and its progression. EXPERIMENTAL DESIGN: Five common nonsynonymous single nucleotide polymorphisms (Arg194Trp, Arg280His, and Arg399Gln for XRCC1; Asp148Glu for APE1; and Val762Ala for ADPRT) were genotyped in Chinese DTC cases and controls. RESULTS: The XRCC1-194Trp/Trp genotype showed a significantly increased risk for DTC (odds ratio, 1.85; 95% confidence interval, 1.11-3.07; P = 0.018). Subset analysis based on regional LN metastasis showed that the genetic effect came primarily from the subjects with LN metastasis (odds ratio, 4.54; 95% confidence interval, 2.11-9.79; P = 0.0001), but no significant association for subjects without LN metastasis. The other four single nucleotide polymorphisms did not show significant results. Haplotype analysis of XRCC1 polymorphisms yielded a significant result (P = 0.004), especially in the subjects with LN metastasis (P = 0.0002). Moreover, we found that XRCC1-194Trp and ADPRT-762Ala variants collectively contributed to an increased risk of the disease and LN metastasis, with the combined variant homozygotes exhibiting the highest 3.18-fold risk for DTC (P = 0.046) and 9.25-fold risk for DTC with LN metastasis (P = 0.004). CONCLUSIONS: The XRCC1 polymorphisms, especially the 194Trp allele, may have an effect on DTC development and progression. This variant can interact with ADPRT-762Ala variant to further substantially increase susceptibility to the disease and regional LN metastasis. Identifying these risk genetic markers could provide more insight into the DTC pathogenesis and may also provide information to develop better prevention and therapeutic strategies.     

核苷酸切除修复通路基因多态性与肺癌易感性

Nucleotide excision repair (NER) pathway is one of the principal ways of the repair of DNA damage. The single nucleotide polymorphisms (SNP) of its key genes such as xeroderma pigmentosum group A (XPA) gene, excision repair cross complementing1 (ERCC1) gene and xeroderma pigmentosum group D (XPD) gene may be associated with differences in the DNA repair capacity and may influence an individual’s risk of lung cancer, because the variant genotype in those polymorphisms might destroy or alter repair function.     

Single-nucleotide polymorphisms in base excision repair, nucleotide excision repair, and double strand break genes as markers for response to radiotherapy in patients with Stage I to II head-and-neck cancer

PURPOSE: Polymorphisms in DNA repair genes can influence response to radiotherapy. We analyzed single-nucleotide polymorphisms (SNP) in nine DNA repair genes in 108 patients with head-and-neck cancer (HNSCC) who had received radiotherapy only. METHODS AND MATERIALS: From May 1993 to December 2004, patients with Stage I and II histopathologically confirmed HNSCC underwent radiotherapy. DNA was obtained from paraffin-embedded tissue, and SNP analysis was performed using a real-time polymerase chain reaction allelic discrimination TaqMan assay with minor modifications. RESULTS: Patients were 101 men (93.5%) and 7 (6.5%) women, with a median age of 64 years (range, 40 to 89 years). Of the patients, 76 (70.4%) patients were Stage I and 32 (29.6%) were Stage II. The XPF/ERCC1 SNP at codon 259 and XPG/ERCC5 at codon 46 emerged as significant predictors of progression (p = 0.00005 and 0.049, respectively) and survival (p = 0.0089 and 0.0066, respectively). Similarly, when variant alleles of XPF/ERCC1, XPG/ERCC5 and XPA were examined in combination, a greater number of variant alleles was associated with shorter time to progression (p = 0.0003) and survival (p = 0.0002). CONCLUSIONS: Genetic polymorphisms in XPF/ERCC1, XPG/ERCC5, and XPA may significantly influence response to radiotherapy; large studies are warranted to confirm their role in HNSCC.     

Polymorphisms in nucleotide excision repair genes and DNA repair capacity phenotype in sisters discordant for breast cancer.

Interindividual differences in DNA repair capacity (DRC) may play a critical role in breast cancer risk. Previously, we determined that DRC measured via removal of in vitro-induced benzo[a]pyrene diolepoxide-DNA adducts in lymphoblastoid cell lines was lower in cases compared with controls among sisters discordant for breast cancer from the Metropolitan New York Registry of Breast Cancer Families. We have now determined genotypes for seven single nucleotide polymorphisms in five nucleotide excision repair genes, including Xeroderma pigmentosum complementation group A (XPA +62T>C), group C (XPC Lys939Gln and Ala499Val), group D (XPD Asp312Asn and Lys751Gln), and group G (XPG His1104Asp) and ERCC1 (8092 C>A) in a total of 160 sister pairs for whom DRC phenotype data were available. Overall, there were no statistically significant differences in average DRC for most of the genotypes. A final multivariate conditional logistic model, including three single nucleotide polymorphisms (XPA +62T>C, XPC Ala499Val, and XPG His1104Asp) and smoking status, only modestly predicted DRC after adjusting for case-control status and age of blood donation. The overall predictive accuracy was 61% in the model with a sensitivity of 78% and specificity of 39%. These findings suggest that those polymorphisms we have investigated to date in nucleotide excision repair pathway genes explain only a small amount of the variability in DRC.     

First evidence for digenic inheritance in hereditary colorectal cancer by mutations in the base excision repair genes

Biallelic mutations in the base excision repair gene Mut Y homologue (MUTYH) are responsible for variable recessively inherited phenotypes of polyposis. Beside MUTYH, the proteins 8-oxo-guanine DNA glycosylase (OGG1) and MTH1 (or NUDT1) are also involved in the repair of 7,8-dihydro-8-oxoguanine (8-oxo-G), previous studies, however, only found missense mutations of unclear pathogenicity in either MTH1 or OGG1. To investigate the role of a defective 8-oxo-G repair we performed a germline mutation screening in the genes OGG1, MTH1 and MUTYH, in 81 patients with a clinical phenotype ranging from attenuated or atypical adenomatous polyposis coli including hyperplastic polyps to hereditary non-polyposis colorectal cancer (HNPCC) type X syndrome without mono- or biallelic mutations in either APC, MUTYH or the DNA mismatch repair genes.We describe here the first pathogenic germline mutation in OGG1, a splice site mutation affecting exon 1, which was inherited from the father, in combination with a maternal MUTYH missense mutation p.Ile223Val in a female patient with advanced synchronous colon cancer and adenomas at the age of 36 years pointing towards digenic inheritance for colorectal cancer (CRC) predisposition.Monoallelic missense mutations in MTH1 (3x), OGG1 (2x), or MUTYH (3x) were identified in 10 patients (12%), three of them were novel.Our findings indicate that mutations in other genes of the 8-oxo-G repair beside MUTYH are involved in CRC predisposition. Oligogenic inheritance affecting genes of a certain repair pathway might therefore be the missing link between monogenic and polygenic traits.     

Polymorphisms in base excision repair genes and thyroid cancer risk

Thyroid cancer (TC) is the most frequent endocrine malignancy, accounting however for only 1-2% of all human cancers, and the best-established risk factor for TC is radiation exposure, particularly during childhood. Since the BER pathway seems to play an important role in the repair of DNA damage induced by IR and other genotoxicants, we carried out a hospital-based case-control study in order to evaluate the potential modifying role of 6 BER polymorphisms on the individual susceptibility to non-familial TC in 109 TC patients receiving iodine-131, and 217 controls matched for age (±2 years), gender and ethnicity. Our results do not reveal a significant involvement of XRCC1 Arg194Trp and Arg399Gln, OGG1 Ser326Cys, APEX1 Asp148Glu, MUTYH Gln335His and PARP1 Val762Ala polymorphisms on the individual susceptibility towards TC, mostly in aggreement with the limited available evidence. By histological stratification analyis, we observed that the association between the presence of heterozygozity in the MUTYH Gln335His polymorphism and TC risk almost reached significance for the papillary subtype of TC. This was the first time that the putative association between this polymorphism and TC susceptibility was evaluated. However, since the sample size was modest, the possibility of a type I error should not be excluded and this result should, therefore, be interpreted with caution. More in depth studies involving larger populations should be pursued in order to further clarify the potential usefulness of the MUTYH Gln335His genotype as a predictive biomarker of susceptibility to TC and the role of the remaining BER polymorphisms on TC susceptibility.