Research Article: Inherited variants in genes somatically mutated in thyroid cancer

Date Published: April 14, 2017

Publisher: Public Library of Science

Author(s): Chiara Campo, Aleksandra Köhler, Gisella Figlioli, Rossella Elisei, Cristina Romei, Monica Cipollini, Franco Bambi, Kari Hemminki, Federica Gemignani, Stefano Landi, Asta Försti, Amanda Ewart Toland.

http://doi.org/10.1371/journal.pone.0174995

Abstract

Tumour suppressor genes when mutated in the germline cause various cancers, but they can also be somatically mutated in sporadic tumours. We hypothesized that there may also be cancer-related germline variants in the genes commonly mutated in sporadic well-differentiated thyroid cancer (WDTC).

We performed a two-stage case-control association study with a total of 2214 cases and 2108 healthy controls from an Italian population. By genotyping 34 single nucleotide polymorphisms (SNPs), we covered a total of 59 missense SNPs and SNPs located in the 5′ and 3′ untranslated regions (UTRs) of 10 different genes.

The Italian1 series showed a suggestive association for 8 SNPs, from which three were replicated in the Italian2 series. The meta-analysis revealed a study-wide significant association for rs459552 (OR: 0.84, 95%CI: 0.75–0.94) and rs1800900 (OR: 1.15, 95%CI: 1.05–1.27), located in the APC and GNAS genes, respectively. The APC rs459552 is a missense SNP, located in a conserved amino acid position, but without any functional consequences. The GNAS rs1800900 is located at a conserved 5’UTR and according to the experimental ENCODE data it may affect promoter and histone marks in different cell types.

The results of this study yield new insights on WDTC, showing that inherited variants in the APC and GNAS genes can play a role in the etiology of thyroid cancer. Further studies are necessary to better understand the role of the identified SNPs in the development of WDTC and to functionally validate our in silico predictions.

Partial Text

Thyroid cancer (TC) is a common endrocrine malignancy. The majority of all thyroid cancers are well-differentiated (WDTC). Among them the most frequent subtype is papillary TC (PTC), followed by follicular TC (FTC); they represent 80–84% and 6–10% of all thyroid carcinomas, respectively [1]. The incidence of TC in the world has been increasing in recent years and it accounts for about 1% of all oncological diseases based on the 2012 GLOBOCAN data [2]. Explanations for the increasing thyroid cancer incidence are controversial [3]. Some experts suggest that the rise in the number of new cancers is due to the increased diagnostic intensity; other experts believe that it is associated to lifestyle changes. Many individual and environmental factors have been considered as risk factors for TC. Indeed, thyroid gland seems to be an organ particularly vulnerable to ionizing radiation and the risk for TC in individuals exposed to radiation at young age persists throughout life [4,5]. Benign nodules/adenomas and goiter seem to have an important role in the predisposition to TC [6], as well as an inherited genetic susceptibility [7,8]. Common genetic variants in low-penetrance genes may interact with each other and with the environment, regulating TC susceptibility [9,10].

A case-control association study was conducted with patients with sporadic WDTC, mainly PTC, and healthy controls from an Italian population. The two subtypes, papillary and follicular TC, were not analyzed separately due to the small number of FTC (11% of cases). Genotype distribution of three SNPs (rs3864004 in CTNNB1; rs2227983 and rs10228436 in EGFR) in controls deviated from HWE (p <0.005) and they were excluded from further analyses. The associations according to the allelic model between the SNPs and WDTC are shown in Table 1. The analysis adjusted for the covariates age and sex, revealed a protective role (pValue <0.05) for 5 SNPs: rs459552 within the APC gene; rs884904 within EGFR; rs8022600 and rs2268477 within TSHR; rs7229678 within the SMDA4 gene. An increased risk of WTDC (pValue <0.05) was found for the rare allele carriers of rs7144481 within TSHR gene, and of rs1800900 and rs7121 within the GNAS gene. To identify new risk variants predisposing to WDTC we investigated genes somatically mutated in the disease for inherited germline polymorphisms, and performed an association study in two case-control sets from Italy. By genotyping of 34 SNPs, we got information of 53 missense SNPs and SNPs located in the 5’ and 3’UTRs of 10 different genes. The Italian1 series showed a suggestive association for 8 SNPs and three of them provided evidence of association in the replication set. Finally, the meta-analysis revealed a study-wide significant association for rs459552 and rs1800900, in the APC and GNAS genes, respectively.   Source: http://doi.org/10.1371/journal.pone.0174995

 

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