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.Nonmedullary thyroid carcinoma (NMTC) is a welldifferentiated thyroid cancer of follicular cell origin [either papillary thyroid carcinoma (PTC) or follicular thyroid carcinoma (FTC)], which represents the most common endocrine malignancy. The annual incidence rate throughout the world ranges from 0.5 to 10 cases per 100,000 people and there is a twofold to fourfold higher incidence of new thyroid cancer cases in women than in men.1 In Europe, thyroid cancer affects 47,240 individuals annually, with an estimated mortality rate of 6,366 patients each year.2 The incidence of thyroid cancer is increasing, with one of the fastest increasing rates among common cancers. Improvement in cancer diagnosis can partly explain the phenomenon. However, early diagnosis alone is unlikely to account for this increase, and environmental factors must also play a role. The major known environmental risk factor for PTC, which accounts for about 80% of all thyroid cancers, 1 is prior exposure to radiation, with a dose-dependent effect on cancer risk. Other risk factors for PTC include iodine deficiency and excess, previous history of benign thyroid disease, such as nodules and autoimmune thyroid disease, as well as a family history. Indeed, epidemiological studies have shown that the risk of thyroid cancer has a higher familial relative risk than any

Wiek zachorowania i płeć jako czynniki modyfikujące związek polimorfizmów zlokalizowanych na chromosomie 9q22 i 14q13 z rakiem brodawkowatym tarczycy

“…Similar results were obtained by Jones et al [13], who showed that carriers of haplotypes consisting of both risk alleles of rs965513 and rs1867277 in a population from the United Kingdom had the highest risk of developing thyroid cancer [13]. A significant association also was observed for a haplotype in 9q22 consisting of a FOXE1 polymorphism: rs965513/ rs10759944/rs1867277 in thyroid cancer families [14]. In our study, some differences in the genotype distributions of rs965513 were observed between younger (diagnosed at ≤ 45 years of age) and older (diagnosed at > 45 years of age) patients, although these differences were not significant after Bonferroni correction.…”

“…The association of rs965513 and rs944289 with PTC was analysed by Liyanarachchi et al in cohorts from Poland and the United States [2], with results that are in accordance with our study. The association of rs965513, rs1867277, rs944289, and rs1443434 with PTC has been confirmed in different populations in recent years [8][9][10][11][12][13][14][15][16][17]. Moreover, four meta-analyses concerning the roles of rs965513, rs1867277, and rs944289 in PTC have been published: the association of rs965513 has been confirmed among both Caucasians and Asians, rs1867277 SNP was ana-…”

Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer

“…The association between rs965513 and thyroid cancer risk has been independently confirmed in different populations (5)(6)(7)(8)(9)(10)(11). The association was also observed in familial PTC and in patients with radiation-induced PTC (12)(13)(14)(15). SNP rs965513 resides ∼60 kb upstream of forkhead box E1 (FOXE1) (also known as thyroid transcription factor 2), a critical transcription factor (TF) in thyroid development, differentiation, and function (16)(17)(18)(19).…”

Familial non-medullary thyroid cancer: unraveling the genetic maze

“…SNPs (rs965513 and rs10759944) at 9p22.33 near FOXE1 showed the most consistent association with FNMTC using familybased association test (FBAT), modified quasi-likelihood score (MQLS) and logistic-normal model (LNM) (Bonora et al 2014). The previously reported SNP rs944289 from sporadic PTC and FTC GWAS (Gudmundsson et al 2009) was not shown to be associated with FNMTC in this study (Bonora et al 2014).…”