Association of Polymorphisms in ERCC2 Gene with Non-Familial Thyroid Cancer Risk

Abstract

The ERCC2 protein is an evolutionary conserved ATPdependent helicase that is associated with a TFIIH transcription factor complex and plays an important role in nucleotide excision repair. Mutations in this gene are responsible for xeroderma pigmentosum and also for Cocayne syndrome and trichothiodystrophy. Several single nucleotide polymorphisms have been identified in the ERCC2 locus. Among them, a G23591A polymorphism in the codon 312 results in an Asp ! Asn substitution in a conserved region and a A35931C polymorphism in the codon 751 results in a Lys ! Gln substitution. Because these polymorphisms have been associated with an increased risk for several types of cancers, we carried out an hospital based case-control study in a Caucasian Portuguese population to evaluate the potential role of these polymorphisms on the individual susceptibility to thyroid cancer. The results obtained did not reveal a significant association between each individual polymorphism studied (G23591A and A35931C) and an increased thyroid cancer risk, but individuals homozygous for non-wild-type variants are overrepresented in patients group. The evaluation of the different haplotypes generated by these polymorphisms showed that individuals simultaneously homozygous for rare variants of both polymorphisms have an increased risk for thyroid cancer [adjusted odds ratio (OR) 3.084; 95% confidence interval (95% CI), 1.347-7.061; P = 0.008] and for papillary thyroid -type tumors (adjusted OR, 2.997; 95% CI, 1.235-7.272; P = 0.015) but not for follicular thyroid -type tumors. These results suggest that genetic polymorphisms in this gene might be associated with individual susceptibility towards thyroid cancer, mainly papillary-type tumors, but larger studies are required to confirm these results. (Cancer Epidemiol Biomarkers Prev 2005;14(10):2407 -12)

DNA Repair Perspectives in Thyroid and Breast Cancer: The Role of DNA Repair Polymorphisms

“…In a previous report, we found a significant association between a haplotype of two SNPs (Asp312Asn and Lys751Gln) in ERCC2 gene, and thyroid cancer risk (Silva et al, 2005) suggesting that this pathway may be relevant for thyroid carcinogenesis. Later we also conducted another study including more SNPs in different genes of NER (CCNH Val270Ala, CDK7 Asn33Asn, RAD23B Ala249Val, ERCC1 Gln504Lys, ERCC4 Arg415Gln, ERCC5 Asp1104His, ERCC5 Cys526Ser, ERCC6 Arg1230Pro, ERCC6 Gln1413Arg, XPC Ala499Val and XPC Lys939Gln) on the individual susceptibility to non-familial thyroid cancer (manuscript in preparation), where we showed that patients carrying at least one variant allele of CCNH Val270Ala polymorphism seems to be at increased risk for thyroid cancer.…”

“…These genes are usually involved in the metabolism of environmental carcinogens, in the repair of DNA lesions induced by exogenous and endogenous carcinogens, and in the control of the cell cycle. Individual polymorphic forms in those genes have been associated with individual susceptibility to different types of cancer namely in breast and thyroid cancer (Conde et al, 2009;Gaspar et al, 2004;Pabalan et al, 2010;Peng et al, 2011;Silva et al, 2005;Silva et al, 2006b;Silva et al, 2006a;Silva et al, 2009;Silva et al, 2010;Silva et al, 2007). Several enzymes have evolved for the detoxification of xenobiotic compounds, and their gene expression is induced in response to the presence of numerous compounds (e.g., polycyclic aromatic hydrocarbons found in tobacco smoke).…”

SNPs/Pools: A methodology for the identification of relevant SNPs in breast cancer epidemiology

“…The individual genotyping of ERCC2 (Lys751Gln), OGG1 (Ser326Cys) and XRCC1 (Arg194Trp and Arg399Gln) was determined by PCR-RFLP. The primers and (17)(18)(19). For all of them the nucleotide polymorphisms resulted in either a gain or loss of restriction site, which therefore allowed the common and variant alleles to be discriminated by RFLP after appropriate restriction enzyme digestion.…”

“…We previously tested the accuracy of pooled DNA analysis using RFLP analysis as a method for the estimation of allelic frequencies, comparing these with the allelic frequencies previously estimated by individual genotyping (17)(18)(19). In the present study we studied several polymorphic genes (ERCC2 Lys751Gln, OGG1 Ser326Cys, XRCC1 Arg194Trp and Arg399Gln) in order to validate the reproducibility of this methodology.…”

The role of common variants of non-homologous end-joining repair genes XRCC4, LIG4 and Ku80 in thyroid cancer risk

“…The most common histological varieties are non-familiar papillary and follicular thyroid carcinomas, being the first one the most frequent of all thyroid follicular-cell malignancies with 85-90% of incidence (3). The only verified cause of thyroid carcinogenesis is exposure to ionizing radiation (IR), though other risk factors have been pointed out as candidates, such as dietary iodine deficiency, hormonal factors, lymphocytic thyroiditis and familiar history (3)(4)(5). Since most of the patients do not show chronic contact with IR and the other factors have non-concordant data, thyroid cancer could be due to sporadic mutations in association with certain exogenous factors.…”