title: The FOXE1 locus is a major genetic determinant for familial nonmedullary thyroid carcinoma.
abstract: Thyroid cancer is the most common endocrine malignancy and nonmedullary thyroid carcinoma (NMTC) represents 90% of all cases. NMTC risk in first-degree relatives of affected cases is elevated fivefold to ninefold. Familial NMTC (FNMTC) accounts for about 3-7% of all thyroid tumors and is a more aggressive clinical entity than its sporadic counterparts. Linkage analysis on high-risk families performed a decade ago mapped several susceptibility loci, but did not lead to the identification of high-penetrance causal germline mutations. More recently, a genome-wide association study (GWAS) identified common single nucleotide polymorphisms (SNPs) affecting the risk of sporadic NMTC. We sought to verify if the newly identified genetic risk factors for NMTC are relevant for FNMTC as well. We genotyped 23 SNPs at 11 candidate loci in 672 subjects belonging to 133 pedigrees with at least two NMTC cases. Statistical analysis was performed using family-based association tests, modified quasi-likelihood score and logistic-normal models. SNPs at 9q22.33 near FOXE1 showed convincing evidence of association with NMTC risk in these high-risk families. The other tested loci resulted negative. These findings confirm the importance of the SNPs identified by recent GWAS on sporadic NMTC on FNMTC as well. However, the proposed FOXE1 causal variants do not show the strongest association signal. Moreover, mutation screening of the FOXE1 coding sequence in the FNMTC cases did not identify rarer causal variants, suggesting that other yet unidentified variants at this locus are involved in FNMTC etiology.
authors.affiliation: Unit of Medical Genetics Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Bonora
authors.forename: Cosmeri
authors.initials: C
authors.lastname: Rizzato
authors.forename: Chiara
authors.initials: C
authors.lastname: Diquigiovanni
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Oudot-Mellakh
authors.forename: Daniele
authors.initials: D
authors.lastname: Campa
authors.forename: Manuela
authors.initials: M
authors.lastname: Vargiolu
authors.forename: Mickaël
authors.initials: M
authors.lastname: Guedj
authors.forename: James D
authors.initials: JD
authors.lastname: McKay
authors.forename: Giovanni
authors.initials: G
authors.lastname: Romeo
authors.forename: Federico
authors.initials: F
authors.lastname: Canzian
authors.forename: Fabienne
authors.initials: F
authors.lastname: Lesueur
mesh_terms: D002851:Chromatography, High Pressure Liquid; D004252:DNA Mutational Analysis; D051858:Forkhead Transcription Factors / Q000235:genetics*; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors
keywords: genetic association study; genetic predisposition; nonmedullary thyroid carcinoma; single nucleotide polymorphisms