The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl

Takahashi, Meiko; Saenko, Vladimir; Rogounovitch, Tatiana; Kawaguchi, Takahisa; Дрозд, Валентина; Takigawa-Imamura, Hisako; Akulevich, Natallia; Ratanajaraya, Chanavee; Mitsutake, Norisato; Takamura, Noboru; Danilova, Larisa; Лущик, М.Л.; Demidchik, Yuri E.; Heath, Simon; Yamada, Ryo; Lathrop, Mark; Matsuda, Fumihiko; Yamashita, Shunichi

doi:10.1093/hmg/ddq123

Cited by 149 publications

(134 citation statements)

References 26 publications

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“…It would therefore be interesting to study thyroid size and morphology in FOXE1-rs1443434 risk allele carriers using ultrasound. Various studies have identified the FOXE1 region as a susceptibility locus for thyroid cancer (33)(34)(35). A recent genome-wide association study identified a polymorphism (i.e.…”

Section: Discussionmentioning

confidence: 99%

A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels

Medici¹,

Deure²,

Verbiest³

et al. 2011

European Journal of Endocrinology

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Objective: Minor variation in serum thyroid hormone (TH) levels can have important effects on various clinical endpoints. Although 45-65% of the inter-individual variation in serum TH levels is due to genetic factors, the causative genes are not well established. We therefore studied the effects of genetic variation in 68 TH pathway genes on serum TSH and free thyroxine (FT 4 ) levels. Design and methods: Sixty-eight genes (1512 polymorphisms) were studied in relation to serum TSH and FT 4 levels in 1121 Caucasian subjects. Promising hits (P!0.01) were studied in three independent Caucasian populations (2656 subjects) for confirmation. A meta-analysis of all four studies was performed. Results: For TSH, eight PDE8B polymorphisms (PZ4!10 K17 ) remained significant in the metaanalysis. For FT 4 , two DIO1 (PZ8!10 K12 ) and one FOXE1 (PZ0.0003) polymorphisms remained significant in the meta-analysis. Suggestive associations were detected for one FOXE1 (PZ0.0028) and three THRB (PZ0.0045) polymorphisms with TSH, and one SLC16A10 polymorphism (PZ0.0110) with FT 4 , but failed to reach the significant multiple-testing corrected P value (P!0.0022 and P!0.0033 respectively). Conclusions: Using a large-scale association analysis, we replicated previously reported associations with genetic variation in PDE8B, THRB, and DIO1. We demonstrate effects of genetic variation in FOXE1 on serum FT 4 levels, and borderline significant effects on serum TSH levels. A suggestive association of genetic variation in SLC16A10 with serum FT 4 levels was found. These data provide insight into the molecular basis of inter-individual variation in TH serum levels.

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Section: Discussionmentioning

confidence: 99%

A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels

Medici¹,

Deure²,

Verbiest³

et al. 2011

European Journal of Endocrinology

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“…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: 87%

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.

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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...

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“…GWAS addressed the genetic predisposition to PTC and found two independent SNPs (rs944289 and rs965513) in the chromosomal regions containing nonannotated genes and a significant association with PTC (Gudmundsson et al 2009, 2012, Takahashi et al 2010. At 3.2-kb downstream of the SNP rs944289 in 14q.13.3, Albert de la Chapelle and his group identified a lincRNA gene and named it PTCSC3.…”

Section: Ptcsc3 (Papillary Thyroid Carcinoma Susceptibility Candidate 3)mentioning

confidence: 99%

Long noncoding RNAs: emerging players in thyroid cancer pathogenesis

Murugan

Munirajan

Alzahrani

2018

Endocrine-Related Cancer

110

103

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Thyroid cancer continues to be the most common malignancy of endocrine glands. The incidence of thyroid cancer has risen significantly over the past 4 decades and has emerged as a major health issue. In recent years, significant progress has been achieved in our understanding of the molecular mechanisms of thyroid carcinogenesis, resulting in significant diagnostic, prognostic and therapeutic implications; yet, it has not reached a satisfactory level. Identifying novel molecular therapeutic targets and molecules for diagnosis and prognosis is expected to advance the overall management of this common malignancy. Long noncoding RNAs (lncRNAs) are implicated in the regulation of various key cellular genes involved in cell differentiation, proliferation, cell cycle, apoptosis, migration and invasion mainly through modulation of gene expression. Recent studies have established that lncRNAs are deregulated in thyroid cancer. In this review, we discuss extensively the tumor-suppressive (for example, LINC00271, MEG3, NAMA, PTCSC1/2/3, etc.) and oncogenic (for example, ANRIL, FAL1, H19, PVT1, etc.) roles of various lncRNAs and their possible disease associations implicated in thyroid carcinogenesis. We briefly summarize the strategies and mechanisms of lncRNA-targeting agents. We also describe the potential role of lncRNAs as prospective novel therapeutic targets, and diagnostic and prognostic markers in thyroid cancer.

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The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl

Cited by 149 publications

References 26 publications

A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels

A large-scale association analysis of 68 thyroid hormone pathway genes with serum TSH and FT4 levels

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

Long noncoding RNAs: emerging players in thyroid cancer pathogenesis

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