<scp><i>FOXE1</i></scp> polymorphisms are associated with familial and sporadic nonmedullary thyroid cancer susceptibility

Tomaz, Rute; Sousa, Inês; Silva, Joana G.; Santos, Catarina; Teixeira, Manuel R.; Leite, Valeriano; Cavaco, Branca

doi:10.1111/j.1365-2265.2012.04505.x

Cited by 58 publications

(51 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is worth noting that among GWAS-derived variants, rs965513 shows the strongest association with sporadic, familial, and radiation-induced PTC (4,12,15). However, advancing from the genetic association to an understanding of the functional biological process has been challenging (23).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

mentioning

confidence: 92%

See 1 more Smart Citation

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

Liyanarachchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The [A] allele of SNP rs965513 in 9q22 has been consistently shown to be highly associated with increased papillary thyroid cancer (PTC) risk with an odds ratio of ∼1.8 as determined by genome-wide association studies, yet the molecular mechanisms remain poorly understood. Previously, we noted that the expression of two genes in the region, forkhead box E1 (FOXE1) and PTC susceptibility candidate 2 (PTCSC2), is regulated by rs965513 in unaffected thyroid tissue, but the underlying mechanisms were not elucidated. Here, we finemapped the 9q22 region in PTC and controls and detected an ∼33-kb linkage disequilibrium block (containing the lead SNP rs965513) that significantly associates with PTC risk. Chromatin characteristics and regulatory element signatures in this block disclosed at least three regulatory elements functioning as enhancers. These enhancers harbor at least four SNPs (rs7864322, rs12352658, rs7847449, and rs10759944) that serve as functional variants. The variant genotypes are associated with differential enhancer activities and/or transcription factor binding activities. Using the chromosome conformation capture methodology, long-range looping interactions of these elements with the promoter region shared by FOXE1 and PTCSC2 in a human papillary thyroid carcinoma cell line (KTC-1) and unaffected thyroid tissue were found. Our results suggest that multiple variants coinherited with the lead SNP and located in long-range enhancers are involved in the transcriptional regulation of FOXE1 and PTCSC2 expression. These results explain the mechanism by which the risk allele of rs965513 predisposes to thyroid cancer.thyroid cancer | genetic susceptibility | long-range enhancer | functional variants | SNP rs965513 P apillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, accounting for >80% of all thyroid malignancy. It is estimated that 62,450 individuals in the United States will be diagnosed with thyroid cancer in 2015 (www.cancer. org/Research/CancerFactsFigures/index). Although PTC is clearly influenced by both genetic and environmental factors, genetic predisposition plays a major role as evidenced by case-control studies (1-3).Genome-wide association studies (GWASs) have linked SNP rs965513 in 9q22 to thyroid cancer, mainly PTC. The odds ratio (OR) for this SNP is as high as ∼1.8 (4). The association between rs965513 and thyroid cancer risk has been independently confirmed in different populations (5-11). The association was also observed in familial PTC and in patients with radiation-induced PTC (12-15). 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). It has been repeatedly proposed that FOXE1 is involved in the tumorigenesis of PTC (11,19,20). A DNA variant (rs1867277) in the promoter region of FOXE1 was reported as a functional variant involved in transcriptional regulation of FOXE1 (19). However, these studi...

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 92%

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

Liyanarachchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Information about the family history of thyroid cancer was obtained from the patients and/or from hospital records. Sixty-six families, the majority previously reported (15), were included in this study. NMTC frequency in these families was as follows: one family had five members affected, five had four members affected, 11 had three members affected and the remaining 49 families had two affected members.…”

Section: Clinicopathological Datamentioning

confidence: 99%

“…Recently, we have found evidence of an association between common variants of the FOXE1 gene and FNMTC susceptibility. This gene encodes the thyroid transcription factor FOXE1, which, together with NKX2-1, HHEX and PAX8, is required for thyroid differentiation and function (15).…”

Section: Introductionmentioning

confidence: 99%

Familial vs sporadic papillary thyroid carcinoma: a matched-case comparative study showing similar clinical/prognostic behaviour

Pinto

Silva²,

Henrique

et al. 2014

European Journal of Endocrinology

Self Cite

View full text Add to dashboard Cite

Objective: Familial non-medullary thyroid cancer has been proposed as an aggressive clinical entity. Our aim in this study is to investigate potential distinguishing features as well as the biological and clinical aggressiveness of familial vs sporadic papillary thyroid carcinoma (PTC). We assessed clinicopathological characteristics, outcome measures and DNA ploidy. Design: A matched-case comparative study. Methods: A series of patients with familial PTC (nZ107) and two subgroups, one with three or more affected elements (nZ32) and another including index cases only (nZ61), were compared with patients with sporadic PTC (nZ107), matched by age, gender, pTNM disease extension and approximate follow-up duration. Histological variant, extrathyroidal extension, vascular invasion, tumour multifocality and bilateral growth were evaluated. Ploidy pattern was analysed in available samples by DNA flow cytometry. The probabilities of disease-free survival (DFS) and overall survival (OS) were estimated according to the Kaplan-Meier (K-M) method. Results: No patient with familial PTC died of disease during follow-up (median, 72 months), contrarily to five patients (4.7%) (PZ0.06) with sporadic PTC (median, 90 months). There was a significantly higher tumour multifocality in familial PTC (index cases subgroup) vs sporadic PTC (PZ0.035), and a trend, in the familial PTC cohort with three or more affected elements, to show extrathyroidal extension (PZ0.054) more frequently. No difference was observed in DNA ploidy status. The K-M analyses showed no significant differences between both entities in relation to DFS or OS. Conclusion: Apart from multifocality, familial PTC appears to have similar clinical/prognostic behaviour when compared with sporadic forms of the disease.

show abstract

“…As a gene with a single exon located at chromosome 9q22.33 [7], FOXE1 (Forkhead Box E1, also known as Thyroid transcription factor 2), is a thyroid-specific forkhead transcription factor that is essential for thyroid gland development, as well as for the maintenance of the thyroid differentiated state in adults [8] FOXE1 is highly expressed in thyroid follicular cells [9] and lots of study data showed that this gene is crucial in the initiation of specific tumors, such as pancreatic cancer, cutaneous squamous cell carcinoma and thyroid neoplasms [10]. Some studies also supposed that upregulation of FOXE1 could play a role in the malignant behaviour of thyroid cells [11], and some case-control studies have been performed to investigate the role of SNP of FOXE1 (rs1867277) in the genetic susceptibility of both PTC and FTC.…”

Section: Introductionmentioning

confidence: 99%

Association between FOXP3, FOXE1 Gene Polymorphisms and Risk of Differentiated Thyroid Cancer in Chinese Han Population

Zheng¹,

Zhang²

2015

Mol Biol

View full text Add to dashboard Cite

show abstract

FOXE1 polymorphisms are associated with familial and sporadic nonmedullary thyroid cancer susceptibility

Abstract: We found compelling evidence of association between FOXE1 variants and thyroid cancer risk in the Portuguese population. To our knowledge, this is the first study supporting the association of this locus with both sporadic and familial NMTC susceptibility.

Cited by 58 publications

References 37 publications

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

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

Familial vs sporadic papillary thyroid carcinoma: a matched-case comparative study showing similar clinical/prognostic behaviour

Association between FOXP3, FOXE1 Gene Polymorphisms and Risk of Differentiated Thyroid Cancer in Chinese Han Population

Contact Info

Product

Resources

About