Association of Polymorphisms in ERCC2 Gene with Non-Familial Thyroid Cancer Risk (original) (raw)
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Association of Polymorphisms in ERCC2 Gene with Non-Familial Thyroid Cancer Risk
Cancer Epidemiology Biomarkers & Prevention, 2005
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
Journal of Medical Genetics, 2012
Five single nucleotide polymorphisms (SNPs) associated with thyroid cancer (TC) risk have been reported: rs2910164 (5q24); rs6983267 (8q24); rs965513 and rs1867277 (9q22); and rs944289 (14q13). Most of these associations have not been replicated in independent populations and the combined effects of the SNPs on risk have not been examined. This study genotyped the five TC SNPs in 781 patients recruited through the TCUKIN study. Genotype data from 6122 controls were obtained from the CORGI and Wellcome Trust Case-Control Consortium studies. Significant associations were detected between TC and rs965513A (p¼6.35310 À34), rs1867277A (p¼5.90310 À24), rs944289T (p¼6.95310 À7), and rs6983267G (p¼0.016). rs6983267 was most strongly associated under a recessive model (P GG vs GT + TT ¼0.004), in contrast to the association of this SNP with other cancer types. However, no evidence was found of an association between rs2910164 and disease under any risk model (p>0.7). The rs1867277 association remained significant (p¼0.008) after accounting for genotypes at the nearby rs965513 (p¼2.3310 À13) and these SNPs did not tag a single high risk haplotype. The four validated TC SNPs accounted for a relatively large proportion (w11%) of the sibling relative risk of TC, principally owing to the large effect size of rs965513 (OR 1.74).
Novel genetic variants in differentiated thyroid cancer and assessment of the cumulative risk
Scientific Reports, 2015
A genome-wide association study (GWAS) performed on a high-incidence Italian population followed by replications on low-incidence cohorts suggested a strong association of differentiated thyroid cancer (DTC) with single nucleotide polymorphisms (SNPs) at 9q22.33, 2q35, 20q11.22-q12 and 14q24.3. Moreover, six additional susceptibility loci were associated with the disease only among Italians. The present study had two aims, first to identify loci involved in DTC risk and then to assess the cumulative effect of the SNPs identified so far in the Italian population. The combined analysis of the previous GWAS and the present Italian study provided evidence of association with rs7935113 (GALNTL4, OR 5 1.36, 95%CI 1.20-1.53, p-value 5 7.41 3 10 27 ) and rs1203952 (FOXA2, OR 5 1.29, 95%CI 1.16-1.44, p-value 5 4.42 3 10 26 ). Experimental ENCODE and eQTL data suggested that both SNPs may influence the closest genes expression through a differential recruitment of transcription factors. The assessment of the cumulative risk of eleven SNPs showed that DTC risk increases with an increasing number of risk alleles (p-trend 5 3.13 3 10 247 ). Nonetheless, only a small fraction (about 4% on the disease liability scale) of DTC is explained by these SNPs. These data are consistent with a polygenic model of DTC predisposition and highlight the importance of association studies in the discovery of the disease hereditability.
PLoS ONE, 2014
Thyroid cancer has a multifactorial aetiology resulting from the interaction of genetic and environmental factors. Several low penetrance susceptibility genes have been identified but their effects often vary between different populations. Somatic point mutations and translocations of the REarranged during Transfection (RET) proto-oncogene are frequently found in thyroid cancer. The aim of this case-control study was to determine the effect of four well known RET single nucleotide polymorphisms (SNPs) on the risk for differentiated thyroid carcinoma. A total of 545 Portuguese patients and 543 controls were genotyped by PCR and restriction enzyme analysis, for the following SNPs: G691S (exon 11, rs1799939 G/ A), L769L (exon 13, rs1800861 T/G), S836S (exon 14, rs1800862 C/T), and S904S (exon 15, rs1800863 C/G). The minor allele of S836S was overrepresented in patients with papillary thyroid carcinoma (PTC) when compared to controls (OR 1.57; 95% CI 1.05-2.35; p = 0.026). The GGTC haplotype was also overrepresented in PTC (OR 2.51; 95% CI 1.07-5.91; p = 0.029). No associations were found in follicular thyroid carcinoma (FTC). Multivariate logistic regression analysis showed no differences regarding gender, age at diagnosis, lymph node or distant metastasis. However, a near significant overrepresentation of the minor alleles of G691S and S904S was found in patients with tumours greater than 10 mm of diameter at diagnosis. These data suggest that the RET S836S polymorphism in exon 14 and the GGTC haplotype are risk factors for PTC, but not FTC, and that the G691S/S904S polymorphisms might be associated with tumour behaviour.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2016
Linkage analyses and association studies suggested that inherited genetic variations play a role in the development of Differentiated Thyroid Carcinoma (DTC). We combined the results from a Genome-Wide Association Study (GWAS) performed by our group and from published studies on DTC. With a first approach, we evaluated whether a SNP published as associated with the risk of DTC could replicate in our GWAS (using FDR as adjustment for multiple comparisons). With the second approach, meta-analyses were performed between literature and GWAS when both sources suggested an association, increasing the statistical power of the analysis. Moreover, the polygenic risk of the associated SNPs was calculated. rs1799814 (CYP1A1), rs1121980 (FTO), and 3 SNPs within 9q22 (rs965513, rs7048394, and rs894673) replicated the associations described in literature. In addition, the meta-analyses between literature and GWAS revealed ten more SNPs within 9q22, six within FTO, two within SOD1, and single vari...
Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations
Nature Genetics, 2009
In order to search for sequence variants conferring risk of thyroid cancer we conducted a genomewide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 × 10 −27 ) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 × 10 −9 ). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T 4 ) and high concentration of triiodothyronine (T 3 ).
2023
Background: Linkage analyses and association studies suggested that inherited genetic variations play a role in the development of differentiated thyroid carcinoma (DTC). Methods: We combined the results from a genome-wide association study (GWAS) performed by our group and from published studies on DTC. With a first approach, we evaluated whether a SNP published as associated with the risk of DTC could replicate in our GWAS (using FDR as adjustment for multiple comparisons). With the second approach, meta-analyses were performed between literature and GWAS when both sources suggested an association, increasing the statistical power of the analysis. Results: rs1799814 (CYP1A1), rs1121980 (FTO), and 3 SNPs within 9q22 (rs965513, rs7048394, and rs894673) replicated the associations described in the literature. In addition, the meta-analyses between literature and GWAS revealed 10 more SNPs within 9q22, six within FTO, two within SOD1, and single variations within HUS1,
Endocrine Connections, 2012
Thyroid hormone receptors, THRA and THRB, together with the TSH receptor, TSHR, are key regulators of thyroid function. Alterations in the genes of these receptors (THRA, THRB and TSHR) have been related to thyroid diseases, including thyroid cancer. Moreover, there is evidence suggesting that predisposition to differentiated thyroid cancer (DTC) is related to common genetic variants with low penetrance that interact with each other and with environmental factors. In this study, we investigated the association of single nucleotide polymorphisms (SNPs) in the THRA (one SNP), THRB (three SNPs) and TSHR (two SNPs) genes with DTC risk. A case–control association study was conducted with 398 patients with sporadic DTC and 479 healthy controls from a Spanish population. Among the polymorphisms studied, only THRA-rs939348 was found to be associated with an increased risk of DTC (recessive model, odds ratio=1.80, 95% confidence interval=1.03–3.14, P=0.037). Gene–gene interaction analysis us...
Cancer Epidemiology, Biomarkers & Prevention, 2013
Background: Genome-wide association studies have shown that the 8q24 region harbours multiple independent cancer susceptibility loci and it was also defined as the “susceptibility cancer region.” Thus, it could be hypothesized that genetic variants within this region could play a role in the risk of differentiated thyroid carcinoma (DTC). Methods: Six single-nucleotide polymorphisms within 8q24 were analyzed, previously associated with the risk of cancer (i.e., rs6983267, rs1447295, rs10808556, rs7000448, rs13254738, and rs13281615) in a population of 1,250 patients affected by DTC and 1,250 controls from Central and Southern Italy. Results: A strong association between smoking habit and risk of DTC was found [OR, 1.63; 95% confidence interval (CI), 1.39–1.91; P < 10−6]. The polymorphisms rs10808556 and rs1447295 showed an association with the risk of DTC (the strongest were the heterozygotes with OR, 1.38; 95% CI, 1.13–1.68 and OR, 1.35; 95% CI, 1.02–1.78, respectively), but, ov...
TPO genetic variants and risk of differentiated thyroid carcinoma in two European populations
International Journal of Cancer, 2013
Thyroid cancer risk involves the interaction of genetic and environmental factors. The thyroperoxidase (TPO) has a key role in the iodine metabolism, being essential for the thyroid function. Mutations in the TPO gene are common in congenital hypothyroidism, and there are also signs of the implication of TPO in thyroid cancer. We performed a case-control association study of genetic variants in TPO and differentiated thyroid carcinoma (DTC) in 1,586 DTC patients and 1,769 controls including two European populations (Italy: 1,190 DTC and 1,290 controls; Spain: 396 DTC and 479 controls). Multivariate logistic regression analyses were performed separately for each population and each single-nucleotide polymorphism (SNP). From the three studied polymorphisms, significant associations were detected between DTC and rs2048722 and rs732609 in both populations (p < 0.05). In the Italian population, both SNPs showed a negative association (rs2048722, odds ratio [OR] 5 0.79, 95% confidence interval [CI] 5 0.63-1.00, p 5 0.045; rs732609, OR 5 0.72, 95% CI 5 0.55-0.94, p 5 0.016), whereas in the Spanish population, these SNPs showed a positive association (rs2048722, OR 5 1.39, 95% CI 5 1.03-1.89, p 5 0.033; rs732609, OR 5 1.41, 95% CI 5 1.06-1.87, p 5 0.018). The corresponding associations for papillary or follicular thyroid cancer were similar to those for all DTC, within population. No association was detected for the third TPO polymorphism in the Italian and the Spanish populations. Our results, for the first time, point to TPO as a gene involved in the risk of DTC, and suggest the importance of interactions between TPO variants and other unidentified population-specific factors in determining thyroid cancer risk.