title: The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors.
abstract: 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 from a 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[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9)). Functional assays of rs1867277 (NM_004473.3:c.-283G>A) within the FOXE1 5' 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/alphaCREM 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.
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Iñigo
authors.initials: I
authors.lastname: Landa
authors.forename: Sergio
authors.initials: S
authors.lastname: Ruiz-Llorente
authors.forename: Cristina
authors.initials: C
authors.lastname: Montero-Conde
authors.forename: Lucía
authors.initials: L
authors.lastname: Inglada-Pérez
authors.forename: Francesca
authors.initials: F
authors.lastname: Schiavi
authors.forename: Susanna
authors.initials: S
authors.lastname: Leskelä
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pita
authors.forename: Roger
authors.initials: R
authors.lastname: Milne
authors.forename: Javier
authors.initials: J
authors.lastname: Maravall
authors.forename: Ignacio
authors.initials: I
authors.lastname: Ramos
authors.forename: Víctor
authors.initials: V
authors.lastname: Andía
authors.forename: Paloma
authors.initials: P
authors.lastname: Rodríguez-Poyo
authors.forename: Antonino
authors.initials: A
authors.lastname: Jara-Albarrán
authors.forename: Amparo
authors.initials: A
authors.lastname: Meoro
authors.forename: Cristina
authors.initials: C
authors.lastname: del Peso
authors.forename: Luis
authors.initials: L
authors.lastname: Arribas
authors.forename: Pedro
authors.initials: P
authors.lastname: Iglesias
authors.forename: Javier
authors.initials: J
authors.lastname: Caballero
authors.forename: Joaquín
authors.initials: J
authors.lastname: Serrano
authors.forename: Antonio
authors.initials: A
authors.lastname: Picó
authors.forename: Francisco
authors.initials: F
authors.lastname: Pomares
authors.forename: Gabriel
authors.initials: G
authors.lastname: Giménez
authors.forename: Pedro
authors.initials: P
authors.lastname: López-Mondéjar
authors.forename: Roberto
authors.initials: R
authors.lastname: Castello
authors.forename: Isabella
authors.initials: I
authors.lastname: Merante-Boschin
authors.forename: Maria-Rosa
authors.initials: MR
authors.lastname: Pelizzo
authors.forename: Didac
authors.initials: D
authors.lastname: Mauricio
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Antona
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
authors.forename: Xavier
authors.initials: X
authors.lastname: Matías-Guiu
authors.forename: Pilar
authors.initials: P
authors.lastname: Santisteban
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
mesh_terms: D000328:Adult; D001483:Base Sequence; D001665:Binding Sites; D016022:Case-Control Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D013030:Spain; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism*; D051720:Upstream Stimulatory Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; C497181:USF1 protein, human; C497184:USF2 protein, human; D051720:Upstream Stimulatory Factors