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And Other Nucleotide Excision Repair Polymorphisms in Individual Susceptibility to Well-Differentiated Thyroid Cancer

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And Other Nucleotide Excision Repair Polymorphisms in Individual Susceptibility to Well-Differentiated Thyroid Cancer 2458 ONCOLOGY REPORTS 30: 2458-2466, 2013 The role of CCNH Val270Ala (rs2230641) and other nucleotide excision repair polymorphisms in individual susceptibility to well-differentiated thyroid cancer LUÍS S. SANTOS1,2*, BRUNO C. GOMES1*, RITA GOUVEIA1, SUSANA N. SILVA1, ANA P. AZEVEDO1,3, VANESSA CAMACHO1, ISABEL MANITA4, OCTÁVIA M. GIL1,5, TERESA C. FERREIRA6, EDWARD LIMBERT6, JOSÉ RUEFF1 and JORGE F. GASPAR1 1Department of Genetics, Faculty of Medical Sciences, Universidade Nova de Lisboa (UNL), Lisbon; 2Health Sciences Institute, Universidade Católica Portuguesa (UCP), Viseu; 3Department of Clinical Pathology, Hospital de S. Francisco Xavier, Lisbon; 4Unit of Endocrinology, Hospital Garcia de Orta, Almada; 5Unit of Radiological Protection and Safety-Technological and Nuclear Campus, Instituto Superior Técnico, Universidade Técnica de Lisboa (UTL), Loures; 6Department of Nuclear Medicine, Instituto Português de Oncologia de Lisboa, Lisbon, Portugal Received May 3, 2013; Accepted July 5, 2013 DOI: 10.3892/or.2013.2702 Abstract. Well-differentiated thyroid cancer (DTC) is the for heterozygous; OR=2.44, 95% CI=1.07-5.55, for variant most common form of thyroid cancer (TC); however, with the allele carriers). Considering papillary TC, the rs2228001 exception of radiation exposure, its etiology remains largely (XPC) variant genotype was associated with increased risk unknown. Several single nucleotide polymorphisms (SNPs) (OR=2.33, 95% CI=1.05-5.16), while a protective effect have previously been implicated in DTC risk. Nucleotide was observed for rs2227869 (ERCC5) (OR=0.26, 95% excision repair (NER) polymorphisms, despite having been CI=0.08-0.90, for heterozygous; OR=0.25, 95% CI=0.07-0.86, associated with cancer risk at other locations, have received for variant allele carriers). No further significant results were little attention in the context of thyroid carcinogenesis. In order observed. Our results suggest that NER polymorphisms such to evaluate the role of NER pathway SNPs in DTC suscep- as rs2230641 (CCNH) and, possibly, rs2227869 (ERCC5) and tibility, we performed a case-control study in 106 Caucasian rs2228001 (XPC), may influence DTC susceptibility. However, Portuguese DTC patients and 212 matched controls. rs2230641 larger studies are required to confirm these results. (CCNH), rs2972388 (CDK7), rs1805329 (RAD23B), rs3212986 (ERCC1), rs1800067 (ERCC4), rs17655, rs2227869 (ERCC5), Introduction rs4253211 and rs2228529 (ERCC6) were genotyped using TaqMan® methodology, while conventional PCR-RFLP was Thyroid cancer (TC) is a rare neoplasia, but is the most employed for rs2228000 and rs2228001 (XPC). When consid- frequent endocrine malignancy (1). In general, it originates ering all DTC cases, only rs2230641 (CCNH) was associated from thyroid follicular cells and its most common histological with DTC risk; a consistent increase in overall DTC risk was types are papillary carcinoma (≈70-80%) and follicular carci- observed for both the heterozygous genotype (OR=1.89, 95% noma (≈10-20%) (2). Papillary and follicular TC are often CI=1.14-3.14) and the variant allele carriers (OR=1.79, 95% categorized together as non-medullary well-differentiated CI=1.09-2.93). Histological stratification analysis confirmed an thyroid cancer (DTC), and, in contrast to undifferentiated identical effect on follicular TC (OR=2.72, 95% CI=1.19-6.22, (anaplastic) TC, have indolent behaviour and can be treated with high survival rates, particularly if they are localized and small-sized (1). TC can occur in any age group but its inci- dence increases with age (1). This type of cancer (particularly DTC) is 3 times more likely to occur in women than in men Correspondence to: Professor Jorge Francisco Gaspar, Department and, in the past 2 decades, its incidence has increased (1). The of Genetics, Faculty of Medical Sciences, Universidade Nova de best-established cause of thyroid carcinogenesis is exposure to Lisboa (UNL), Rua da Junqueira 100, P-1349-008 Lisbon, Portugal ionizing radiation, although other candidate risk factors such E-mail: [email protected] as dietary iodine deficiency, hormonal factors, benign thyroid *Contributed equally conditions and familial history have also been noted (2). DTC frequency is significantly higher in relatives (particu- Key words: CCNH, DNA repair, genetic susceptibility, nucleotide larly first-degree) of DTC patients compared to the general excision repair, single nucleotide polymorphisms, well-differentiated population (2,3). However, familial DTC accounts for only a thyroid cancer minor percentage of cases (2), suggesting that other genetic risk factors could be involved. Identifying such individual genetic differences so that these may be used as genetic SANTOS et al: ROLE OF NER PATHWAY SNPs IN DTC SUSCEPTIBILITY 2459 susceptibility markers for DTC in the remaining sporadic history of cancer, lifestyle habits (such as smoking, alcohol cases is therefore an important challenge. In line with this, drinking) and exposure to ionizing radiation was collected several DNA polymorphisms in genes involved in endobiotic using a questionnaire administered by trained interviewers. or xenobiotic metabolism (including GST and CYP super- Former smokers were considered as non-smokers if they had families), in hormonal and iodine metabolism (such as TG), given up smoking either 2 years before DTC diagnosis or in cell-cycle control and regulation of apoptosis (such as 2 years before their inclusion as controls. The response rate TP53), in kinase-dependent signaling pathways (such as RET) was >95% for cases and controls. The anonymity of patients and in DNA repair (among others) have been associated with and controls was guaranteed and written informed consent was differential susceptibility to DTC [reviewed in reference (3)]. obtained from all those involved, prior to blood withdrawal, The first genome-wide association study (GWAS) performed in agreement with the Declaration of Helsinki. Approval by on TC identified 2 other polymorphisms located near the the institutional ethics boards of the involved institutions was FOXE1 (TTF-2) and NKX2-1 (TTF-1) genes (which encode mandatory. for thyroid-specific transcription factors) as strong genetic risk markers of sporadic DTC in European populations (4). DNA extraction. Peripheral blood samples of all patients and Since patients with papillary TC present a significant controls were collected into 10 ml heparinized tubes and kept increase in DNA damage (5) and DNA repair mechanisms at -80˚C. Genomic DNA was obtained from each sample are important in correcting such damage, it is reasonable to using a commercially available kit (QIAamp® DNA mini assume that defective DNA repair capacity may contribute to kit; Qiagen) according to the manufacturer's instructions. All DTC risk. Variants in DNA repair genes may affect the DNA DNA samples were stored at -20˚C until analysis. repair capacity and, in fact, several single nucleotide polymor- phisms (SNPs) in almost all DNA repair pathways have been SNP selection. Publicly available databases such as NCBI shown to incrementally contribute to cancer risk (6). Regarding (http://www.ncbi.nlm.nih.gov/snp/), Genecards (http://www. TC, polymorphisms in DNA repair genes such as XRCC1 (7-9) genecards.org) and SNP500Cancer (http://variantgps.nci.nih. and possibly MUTYH (10) (BER pathway), Ku80 (11) (NHEJ gov/cgfseq/pages/snp500.do) were used to search for NER pathway), BRCA1 (12), XRCC3 and possibly RAD51 (13) (HR polymorphisms. Eligible SNP's had to be located either in a pathway) have been associated with either TC or, more specifi- coding or splice region and had to exhibit minor allele frequency cally, DTC risk [reviewed in references (3,14,15)]. (MAF) >0.05 in Caucasian populations. Despite being located Nucleotide excision repair (NER) is a versatile DNA repair on the 3'UTR region, rs3212986 (ERCC1) was also selected mechanism capable of repairing UV light-induced lesions, since it is one of the most extensively studied ERCC1 SNPs bulky DNA adducts, distorting interstrand crosslinks and and evidence exists for functional significance (18,19). In total, even certain oxidative lesions (16). A significant association 9 common nsSNP's, 1 synonymous SNP and 1 SNP located on between an ERCC2 haplotype (rs13181/rs1799793) and TC risk 3'UTR were selected (Table I). (mainly papillary) was previously reported by our team (17), suggesting that NER polymorphisms may also be relevant for Genotyping. rs2230641 (CCNH), rs2972388 (CDK7), thyroid carcinogenesis. However, to our knowledge, no other rs1805329 (RAD23B), rs3212986 (ERCC1), rs1800067 published study has thus far focused on a possible role of NER (ERCC4), rs17655 and rs2227869 (ERCC5), rs4253211 and pathway SNPs in DTC susceptibility. rs2228529 (ERCC6) were genotyped by real-time PCR, using Therefore, we carried out an exploratory hospital-based TaqMan SNP Genotyping Assays (Applied Biosystems). case-control study in a Caucasian Portuguese population to To assure uniformity in genomic DNA content (2.5 ng/µl) evaluate the potential modifying role of a panel of 11 NER in all samples, DNA was quantified using the fluorimetric pathway SNPs (CCNH rs2230641, CDK7 rs2972388, RAD23B Quant-iT™ Picogreen® dsDNA Assay kit (Invitrogen Life rs1805329, ERCC1 rs3212986, ERCC4 rs1800067, ERCC5 Technologies) and a Zenyth 3100 plate reader (Anthos Labtec rs17655 and rs2227869, ERCC6 rs4253211 and rs2228529 and Instruments), according to the manufacturer's recommenda- XPC rs2228000 and rs2228001) on the individual
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