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Author:
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Landa, Iñigo; Ruiz-Llorente, Sergio; Montero-Conde, Cristina; Inglada-Pérez, Lucía; Schiavi, Francesca; Leskelä, Susanna; Pita, Guillermo; Milne, Roger; Maravall Royo, Javier; Ramos, Ignacio; Andía, Víctor; Rodríguez-Poyo, Paloma; Jara-Albarrán, Antonino; Meoro, Amparo; Peso, Cristina del; Arribas, Luis; Iglesias, Pedro; Caballero, Javier; Serrano, Joaquín; Picó, Antonio; Pomares, Francisco; Giménez, Gabriel; López-Mondéjar, Pedro; Castello, Roberto; Merante-Boschin, Isabella; Pelizzo, Maria-Rosa; Mauricio Puente, Dídac; Opocher, Giuseppe; Rodríguez-Antona, Cristina; González- Neira, Anna; Matias-Guiu, Xavier; Santisteban, Pilar; Robledo, Mercedes
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Notes:
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In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied
tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be
differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases
and 525 controls, the former comprising the largest collection of patients with this pathology froma single population studied
to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary
thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent
Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[perallele]
= 1.49; 95%CI = 1.30–1.70; P = 5.961029). Functional assays of rs1867277 (NM_004473.3:c.2283G.A) within the FOXE1
59 UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the
sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which
DREAM/CREB/aCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We
propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in
thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and
thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches
in the GWAS era. |
