Gene Summary

Gene:FOXE1; forkhead box E1
Aliases: TTF2, FOXE2, HFKH4, HFKL5, NMTC4, TITF2, TTF-2, FKHL15
Summary:This intronless gene encodes a protein that belongs to the forkhead family of transcription factors. Members of this family contain a conserved 100-amino acid DNA-binding 'forkhead' domain. The encoded protein functions as a thyroid transcription factor that plays a role in thyroid morphogenesis. Mutations in this gene are associated with the Bamforth-Lazarus syndrome, and with susceptibility to nonmedullary thyroid cancer-4. [provided by RefSeq, Nov 2016]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:forkhead box protein E1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (31)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Up-Regulation
  • Upstream Stimulatory Factors
  • Skin Cancer
  • Cancer DNA
  • Genetic Association Studies
  • Genetic Loci
  • Papillary Carcinoma
  • Chromosome 9
  • thyroid nuclear factor 1
  • Genetic Variation
  • Thyroid Cancer, Papillary
  • Case-Control Studies
  • Forkhead Transcription Factors
  • Transcription Factors
  • Nuclear Proteins
  • Survival Rate
  • Risk Factors
  • Mutation
  • Transcriptional Activation
  • Follicular Adenocarcinoma
  • Sulfites
  • DNA Methylation
  • ras Proteins
  • Genotype
  • Cancer Gene Expression Regulation
  • Polymerase Chain Reaction
  • Cell Differentiation
  • Single Nucleotide Polymorphism
  • Pancreatic Cancer
  • Genetic Predisposition
  • Polymorphism
  • Genome-Wide Association Study
  • DNA Sequence Analysis
  • Biomarkers, Tumor
  • Promoter Regions
  • Adolescents
  • Alleles
  • Carcinoma
  • Messenger RNA
  • DNA-Binding Proteins
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FOXE1 (cancer-related)

Deshpande V, Luebeck J, Nguyen ND, et al.
Exploring the landscape of focal amplifications in cancer using AmpliconArchitect.
Nat Commun. 2019; 10(1):392 [PubMed] Free Access to Full Article Related Publications
Focal oncogene amplification and rearrangements drive tumor growth and evolution in multiple cancer types. We present AmpliconArchitect (AA), a tool to reconstruct the fine structure of focally amplified regions using whole genome sequencing (WGS) and validate it extensively on multiple simulated and real datasets, across a wide range of coverage and copy numbers. Analysis of AA-reconstructed amplicons in a pan-cancer dataset reveals many novel properties of copy number amplifications in cancer. These findings support a model in which focal amplifications arise due to the formation and replication of extrachromosomal DNA. Applying AA to 68 viral-mediated cancer samples, we identify a large fraction of amplicons with specific structural signatures suggestive of hybrid, human-viral extrachromosomal DNA. AA reconstruction, integrated with metaphase fluorescence in situ hybridization (FISH) and PacBio sequencing on the cell-line UPCI:SCC090 confirm the extrachromosomal origin and fine structure of a Forkhead box E1 (FOXE1)-containing hybrid amplicon.

Ock S, Ahn J, Lee SH, et al.
Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation.
Int J Cancer. 2018; 143(10):2458-2469 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
Insulin and insulin-like growth factor (IGF)-1 signaling in the thyroid are thought to be permissive for the coordinated regulation by thyroid-stimulating hormone (TSH) of thyrocyte proliferation and hormone production. However, the integrated role of insulin receptor (IR) and IGF-1 receptor (IGF-1R) in thyroid development and function has not been explored. Here, we generated thyrocyte-specific IR and IGF-1R double knockout (DTIRKO) mice to precisely evaluate the coordinated functions of these receptors in the thyroid of neonates and adults. Neonatal DTIRKO mice displayed smaller thyroids, paralleling defective folliculogenesis associated with repression of the thyroid-specific transcription factor Foxe1. By contrast, at postnatal day 14, absence of IR and IGF-1R paradoxically induced thyrocyte proliferation, which was mediated by mTOR-dependent signaling pathways. Furthermore, we found elevated production of TSH during the development of follicular hyperplasia at 8 weeks of age. By 50 weeks, all DTIRKO mice developed papillary thyroid carcinoma (PTC)-like lesions that correlated with induction of the ErbB pathway. Taken together, these data define a critical role for IR and IGF-1R in neonatal thyroid folliculogenesis. They also reveal an important reciprocal relationship between IR/IGF-1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and, possibly, of papillary carcinoma.

Chen YH, Zhang YQ
Exploration of the association between FOXE1 gene polymorphism and differentiated thyroid cancer: a meta-analysis.
BMC Med Genet. 2018; 19(1):83 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
BACKGROUND: Several association analyses and linkage researches indicated that inherited genetic variations effectively influence differentiated thyroid carcinogenesis.
METHODS: The results from 15 published studies on differentiated thyroid carcinoma (DTC) were combined. The genetic model included rs965513, rs944289 and rs1867277. Meta-analyses were performed and cochran's χ
RESULTS: Significant results were noticed for rs965513(Odds Ratio(OR) = 1.162(1.117, 1.208)), rs944289(OR = 1.082(1.035, 1.131)) and rs1867277(OR = 1.415(1.324, 1.512)). In the subgroup analysis by ethnicity, rs965513 polymorphism conferred that risk of Caucasians (OR = 1.168(1.122, 1.215)) was more than that of East Asians of 1.35 (OR = 0.897(0.680, 1.193)).
CONCLUSION: This meta-analysis revealed that common variations of FOXE1 (rs965513, rs944289 and rs1867277) were risk factors associated with increased DTC susceptibility.

Son HY, Hwangbo Y, Yoo SK, et al.
Genome-wide association and expression quantitative trait loci studies identify multiple susceptibility loci for thyroid cancer.
Nat Commun. 2017; 8:15966 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
Thyroid cancer is the most common cancer in Korea. Several susceptibility loci of differentiated thyroid cancer (DTC) were identified by previous genome-wide association studies (GWASs) in Europeans only. Here we conducted a GWAS and a replication study in Koreans using a total of 1,085 DTC cases and 8,884 controls, and validated these results using expression quantitative trait loci (eQTL) analysis and clinical phenotypes. The most robust associations were observed in the NRG1 gene (rs6996585, P=1.08 × 10

Huynh MT, Boudry-Labis E, Duban B, et al.
WAGR syndrome and congenital hypothyroidism in a child with a Mosaic 11p13 deletion.
Am J Med Genet A. 2017; 173(6):1690-1693 [PubMed] Related Publications
Wilm's tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome, a rare genetic disorder, is caused by the loss of 11p13 region including PAX6 and WT1. We report novel findings in a 28-month-old boy with aniridia, Wilm's tumor, congenital hypothyroidism, and sublingual thyroid ectopia. He was found to have a mosaic 5.28 Mb interstitial deletion of chromosome 11p13 deleting PAX6 and WT1. In order to clarify the mechanism underlying his thyroid dysgenesis, sequence analysis of candidate thyroid developmental genes was performed. We identified a FOXE1: c.532_537delGCCGCC p.(Ala178_Ala179del) variant that predisposes to thyroid ectopia. Taken together, this is the first report of mosaic 11p13 deletion in association with thyroid dysgenesis. We also propose a model of complex interactions of different genetic variants for this particular phenotype in the present patient.

Kato S, Goodman A, Walavalkar V, et al.
Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate.
Clin Cancer Res. 2017; 23(15):4242-4250 [PubMed] Article available free on PMC after 15/11/2019 Related Publications

Roux T, An-Gourfinkel I, Bertrand A, Bielle F
Astrocytic tumor with large cells and worrisome features in two patients with tuberous sclerosis: drastically different diagnoses and prognoses.
Clin Neuropathol. 2017 May/Jun; 36 (2017)(3):102-107 [PubMed] Related Publications
INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare autosomal dominant genetic disease, characterized by the development of benign tumors in several organs. During infancy, 6 - 20% of patients develop brain tumors called subependymal giant cell astrocytoma (SEGA).
CASE REPORTS: Here we present two patients with TSC, who displayed acute intracranial tumors requiring surgery. Although both tumors shared similar histological aspects with large astrocytic cells and worrisome features, immunohistochemical and genetic analysis successfully distinguished an opposite diagnosis for the two patients.

Kinugawa Y, Uehara T, Sano K, et al.
Methylation of Tumor Suppressor Genes in Autoimmune Pancreatitis.
Pancreas. 2017 May/Jun; 46(5):614-618 [PubMed] Related Publications
OBJECTIVES: Autoimmune pancreatitis (AIP) is a representative IgG4-related and inflammatory disease of unknown etiology. To clarify mechanisms of carcinogenesis resulting from AIP, we focused on methylation abnormalities and KRAS mutations in AIP.
METHODS: Six tumor suppressor genes (NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16) that exhibited hypermethylation in pancreatic carcinoma were selected for quantitative SYBR green methylation-specific polymerase chain reaction in 10 AIP specimens, 10 pancreatic adenocarcinoma cases without history of AIP containing carcinoma areas (CAs) and noncarcinoma areas (NCAs), and 11 normal pancreas (NP) samples. KRAS mutation in codons 12, 13, and 61 were also investigated using direct sequencing.
RESULTS: Hypermethylation events (≥10%) were identified in NPTX2, Cyclin D2, FOXE1, TFPI2, ppENK, and p16 in 1, 2, 2, 0, 2, and 0 CA cases, respectively, but not in these 6 candidate genes in AIP, NCA, and NP. However, the TFPI2 methylation ratio was significantly higher in AIP than NCA and NP. Direct sequencing results for KRAS showed no single-point mutations in AIP.
CONCLUSIONS: These are the first studies characterizing methylation abnormalities in AIP. AIP's inflammatory condition may be related to carcinogenesis. Further study will elucidate methylation abnormalities associated with carcinogenesis in AIP.

Hata T, Dal Molin M, Hong SM, et al.
Predicting the Grade of Dysplasia of Pancreatic Cystic Neoplasms Using Cyst Fluid DNA Methylation Markers.
Clin Cancer Res. 2017; 23(14):3935-3944 [PubMed] Article available free on PMC after 15/11/2019 Related Publications

Wang Y, He H, Li W, et al.
MYH9 binds to lncRNA gene PTCSC2 and regulates FOXE1 in the 9q22 thyroid cancer risk locus.
Proc Natl Acad Sci U S A. 2017; 114(3):474-479 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
A locus on chromosome 9q22 harbors a SNP (rs965513) firmly associated with risk of papillary thyroid carcinoma (PTC). The locus also comprises the forkhead box E1 (FOXE1) gene, which is implicated in thyroid development, and a long noncoding RNA (lncRNA) gene, papillary thyroid cancer susceptibility candidate 2 (PTCSC2). How these might interact is not known. Here we report that PTCSC2 binds myosin-9 (MYH9). In a bidirectional promoter shared by FOXE1 and PTCSC2, MYH9 inhibits the promoter activity in both directions. This inhibition can be reversed by PTCSC2, which acts as a suppressor. RNA knockdown of FOXE1 in primary thyroid cells profoundly interferes with the p53 pathway. We propose that the interaction between the lncRNA, its binding protein MYH9, and the coding gene FOXE1 underlies the predisposition to PTC triggered by rs965513.

Cameselle-Teijeiro JM, Rodríguez-Pérez I, Celestino R, et al.
Hobnail Variant of Papillary Thyroid Carcinoma: Clinicopathologic and Molecular Evidence of Progression to Undifferentiated Carcinoma in 2 Cases.
Am J Surg Pathol. 2017; 41(6):854-860 [PubMed] Related Publications
The hobnail variant (HV) of papillary thyroid carcinoma (PTC) is an unusual entity recently proposed as an aggressive variant of PTC. We describe the pathologic and molecular features of 2 cases of HV of PTC. Both tumors presented in stage III (pT3 pN1a M0). The first case was diagnosed in a 62-year-old man, whereas the second was in a 53-year-old woman. Both patients were treated with total thyroidectomy and radioactive iodine. The primary tumors showed a hobnail/micropapillary pattern in ≥50% of the neoplasm, and positivity for TTF-1, TTF-2, thyroglobulin (TG), cyclin D1, and p53. The Ki-67 index was 4.6% and 5%, respectively. In case 1, the tumor disclosed BRAFV600E and TERT C228T (124:G>A) promoter gene mutation, negativity for NRAS, HRAS, and KRAS mutations, and negativity for RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements. After 11 years the patient died with cervical lymph node, bone, and liver metastases. In the liver metastasis, the tumor displayed columnar cell PTC areas (positive for TTF-1, TG, and BRAFV600E) merging with undifferentiated carcinoma (UC) areas (positive for TTF-1 and BRAFV600E; negative for TG). In case 2, the patient died 6 years after treatment with local recurrence and disseminated metastases to the lung, pleura, bone, and liver. The tumor recurrence showed a UC component (positive for cyclin D1 and p53; negative for TTF-1 and TG) with a residual HV of PTC (positive for cyclin D1, p53, TTF-1, and TG). No BRAF, TERT, NRAS, HRAS, nor KRAS mutations were detected in the primary tumor or recurrence in case 2. Our findings suggest that p53-positive HV is a very aggressive form of PTC prone to progression to UC.

Bullock M, Lim G, Li C, et al.
Thyroid transcription factor FOXE1 interacts with ETS factor ELK1 to co-regulate TERT.
Oncotarget. 2016; 7(52):85948-85962 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
BACKGROUND: Although FOXE1 was initially recognized for its role in thyroid organogenesis, more recently a strong association has been identified between the FOXE1 locus and thyroid cancer. The role of FOXE1 in adult thyroid, and in particular regarding cancer risk, has not been well established. We hypothesised that discovering key FOXE1 transcriptional partners would in turn identify regulatory pathways relevant to its role in oncogenesis.
RESULTS: In a transcription factor-binding array, ELK1 was identified to bind FOXE1. We confirmed this physical association in heterologously transfected cells by IP and mammalian two-hybrid assays. In thyroid tissue, endogenous FOXE1 was shown to bind ELK1, and using ChIP assays these factors bound thyroid-relevant gene promoters TPO and TERT in close proximity to each other. Using a combination of electromobility shift assays, TERT promoter assays and siRNA-silencing, we found that FOXE1 positively regulated TERT expression in a manner dependent upon its association with ELK1. Treating heterologously transfected thyroid cells with MEK inhibitor U0126 inhibited FOXE1-ELK1 interaction, and reduced TERT and TPO promoter activity.
METHODOLOGY: We investigated FOXE1 interactions within in vitro thyroid cell models and human thyroid tissue using a combination of immunoprecipitation (IP), chromatin IP (ChIP) and gene reporter assays.
CONCLUSIONS: FOXE1 interacts with ELK1 on thyroid relevant gene promoters, establishing a new regulatory pathway for its role in adult thyroid function. Co-regulation of TERT suggests a mechanism by which allelic variants in/near FOXE1 are associated with thyroid cancer risk.

Peiling Yang S, Ngeow J
Familial non-medullary thyroid cancer: unraveling the genetic maze.
Endocr Relat Cancer. 2016; 23(12):R577-R595 [PubMed] Related Publications
Familial non-medullary thyroid cancer (FNMTC) constitutes 3-9% of all thyroid cancers. Out of all FNMTC cases, only 5% in the syndromic form has well-studied driver germline mutations. These associated syndromes include Cowden syndrome, familial adenomatous polyposis, Gardner syndrome, Carney complex type 1, Werner syndrome and DICER1 syndrome. It is important for the clinician to recognize these phenotypes so that genetic counseling and testing can be initiated to enable surveillance for associated malignancies and genetic testing of family members. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. To date, 4 susceptibility genes have been identified (SRGAP1 gene (12q14), TITF-1/NKX2.1 gene (14q13), FOXE1 gene (9q22.33) and HABP2 gene (10q25.3)), out of which only the FOXE1 and the HABP2 genes have been validated by separate study groups. The causal genes located at the other 7 FNMTC-associated chromosomal loci (TCO (19q13.2), fPTC/ PRN (1q21), FTEN (8p23.1-p22), NMTC1 (2q21), MNG1 (14q32), 6q22, 8q24) have yet to be identified. Increasingly, gene regulatory mechanisms (miRNA and enhancer elements) are recognized to affect gene expression and FNMTC tumorigenesis. With newer sequencing technique, along with functional studies, there has been progress in the understanding of the genetic basis of FNMTC. In our review, we summarize the FNMTC studies to date and provide an update on the recently reported susceptibility genes including novel germline SEC23B variant in Cowden syndrome, SRGAP1 gene, FOXE1 gene and HABP2 genes in non-syndromic FNMTC.

Weinberger P, Ponny SR, Xu H, et al.
Cell Cycle M-Phase Genes Are Highly Upregulated in Anaplastic Thyroid Carcinoma.
Thyroid. 2017; 27(2):236-252 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
BACKGROUND: Anaplastic thyroid carcinoma (ATC) accounts for only 3% of thyroid cancers, yet strikingly, it accounts for almost 40% of thyroid cancer deaths. Currently, no effective therapies exist. In an effort to identify ATC-specific therapeutic targets, we analyzed global gene expression data from multiple studies to identify ATC-specific dysregulated genes.
METHODS: The National Center for Biotechnology Information Gene Expression Omnibus database was searched for high-throughput gene expression microarray studies from human ATC tissue along with normal thyroid and/or papillary thyroid cancer (PTC) tissue. Gene expression levels in ATC were compared with normal thyroid or PTC using seven separate comparisons, and an ATC-specific gene set common in all seven comparisons was identified. We investigated these genes for their biological functions and pathways.
RESULTS: There were three studies meeting inclusion criteria, (including 32 ATC patients, 69 PTC, and 75 normal). There were 259 upregulated genes and 286 downregulated genes in ATC with at least two-fold change in all seven comparisons. Using a five-fold filter, 36 genes were upregulated in ATC, while 40 genes were downregulated. Of the 10 top globally upregulated genes in ATC, 4/10 (MMP1, ANLN, CEP55, and TFPI2) are known to play a role in ATC progression; however, 6/10 genes (TMEM158, CXCL5, E2F7, DLGAP5, MME, and ASPM) had not been specifically implicated in ATC. Similarly, 3/10 (SFTA3, LMO3, and C2orf40) of the most globally downregulated genes were novel in this context, while 7/10 genes (SLC26A7, TG, TSHR, DUOX2, CDH1, PDE8B, and FOXE1) have been previously identified in ATC. We experimentally validated a significant correlation for seven transcription factors (KLF16, SP3, ETV6, FOXC1, SP1, EGFR1, and MAFK) with the ATC-specific genes using microarray analysis of ATC cell lines. Ontology clustering of globally altered genes revealed that "mitotic cell cycle" is highly enriched in the globally upregulated gene set (44% of top upregulated genes, p-value <10
CONCLUSIONS: By focusing on globally altered genes, we have identified a set of consistently altered biological processes and pathways in ATC. Our data are consistent with an important role for M-phase cell cycle genes in ATC, and may provide direction for future studies to identify novel therapeutic targets for this disease.

Ji GH, Cui Y, Yu H, Cui XB
Profiling analysis of FOX gene family members identified FOXE1 as potential regulator of NSCLC development.
Cell Mol Biol (Noisy-le-grand). 2016; 62(11):57-62 [PubMed] Related Publications
Lung cancer is one of the most malignant tumors worldwide with a high mortality rate, which has not been improved since several decades ago. FOX gene family members have been reported to play extensive roles in regulating many biological processes and disorders. In order to clarify the contribution of FOX gene family members in lung cancer biology, we performed expression profiling analysis of FOX gene family members from FOXA to FOXR in lung cancer cell lines and tissue specimens by Real-time PCR, western blot and immunohistochemistry analysis. We found that FOXE1 was the only gene which was over-expressed in six out of eight lung cancer cell lines and human cancer tissue specimens (28 out of 35 cases with higher expression and 7 out of 35 cases with moderate expression). Further investigation showed that MMP2 gene was up-regulated, and autophagy markers such as LC3B, ATG5, ATG12 and BECLIN1, were down-regulated concomitant with the increase of FOXE1. These results implicated that FOXE1 may be an important regulator by targeting autophagy and MMPs pathways in lung cancer development.

Ren Y, Lence-Anta JJ, Pereda CM, et al.
FOXE1 Polymorphism Interacts with Dietary Iodine Intake in Differentiated Thyroid Cancer Risk in the Cuban Population.
Thyroid. 2016; 26(12):1752-1760 [PubMed] Related Publications
BACKGROUND: The incidence of differentiated thyroid cancer (DTC) is low in Cuba, and the contribution of dietary factors to DTC in this population has not been investigated so far. The aim of this study was to evaluate the relationship between dietary iodine intake and DTC with regard to the interaction with environmental factors or some common single nucleotide polymorphisms (SNPs), based on a case-control study carried out in Cuba.
METHODS: A total of 203 cases and 212 controls from the general population were interviewed face-to-face using the dietary intake questionnaire and the photo booklet from the E3N cohort. A specific food composition table was constructed for this study. For each parameter studied, the odds ratio (OR) was stratified on age group and sex, and further adjusted for dietary energy, smoking status, ethnic group, level of education, number of pregnancies, and body surface area.
RESULTS: The risk of DTC was significantly reduced with increasing consumption of fish (p = 0.04), but no association between total dietary iodine intake and DTC risk was evident (p = 0.7). This lack of significant association was true whatever the age, the smoking status, the dietary selenium intake, and the ethnicity (p > 0.05). DTC risk was positively and strongly associated with the number of copies in the minor allele (A) for SNP rs965513 near FOXE1 among people who consumed less iodine than the median (p = 0.005).
CONCLUSION: Overall, the majority of the studied population had an optimal dietary iodine intake. DTC risk was inversely associated with high fish consumption. Furthermore, DTC risk was positively associated with the number of copies in the minor allele (A) of rs965513 among people who consumed less iodine than the median. Because these findings are based on post-diagnostic measures, studies with pre-diagnostic dietary iodine are needed for confirmation.

Weeks AL, Wilson SG, Ward L, et al.
HABP2 germline variants are uncommon in familial nonmedullary thyroid cancer.
BMC Med Genet. 2016; 17(1):60 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
BACKGROUND: The genetic basis of nonsyndromic familial nonmedullary thyroid cancer (FNMTC) is poorly understood. A recent study identified HABP2 as a tumor suppressor gene and identified a germline variant (G534E) in an extended FNMTC kindred. The relevance of this to other FNMTC kindreds is uncertain.
METHODS: Sanger sequencing was performed on peripheral blood DNA from probands from 37 Australian FNMTC kindreds to detect the G534E variant. Whole exome data from 59 participants from 20 kindreds were examined for mutations in HABP2 and the thyroid cancer susceptibility genes SRGAP1, NKX2-1, SRRM2 and FOXE1. The population prevalence of the G534E variant in HABP2 was examined in two independent cohorts.
RESULTS: Heterozygosity for the G534E variant in HABP2 was found in 1 of 37 probands (2.7 %), but did not cosegregate with disease in this kindred, being absent in the proband's affected sister. From whole exome data, pathogenic mutations were not identified in HABP2, SRGAP1, NKX2-1, SRRM2 or FOXE1. Heterozygosity for the G534E variant in HABP2 was present in 7.6 % of Busselton Health Study participants (N = 4634, unknown disease status) and 9.3 % of TwinsUK participants (N = 1195, no history of thyroid cancer).
CONCLUSIONS: The G534E variant in HABP2 does not account for the familial nature of NMTC in Australian kindreds, and is common in the general population. Further research is required to elucidate the genetic basis of nonsyndromic FNMTC.

Raimundo J, Alvelos MI, Azevedo T, et al.
Association of FOXE1 polyalanine repeat region with thyroid cancer is dependent on tumour size.
Clin Endocrinol (Oxf). 2017; 86(2):243-246 [PubMed] Related Publications
OBJECTIVE: Polymorphisms in the thyroid transcription factor forkhead factor E1 (FOXE1) gene have been implicated in the genetic susceptibility to differentiated thyroid cancer, but little is known about their effect on tumour characteristics. The objective of this study was to determine the contribution of the FOXE1 polyalanine repeat region to the susceptibility to thyroid cancer and to its clinical characteristics.
DESIGN, PATIENTS AND MEASUREMENTS: A total of 500 patients with sporadic thyroid cancer (440 papillary and 60 follicular thyroid carcinoma) and 502 healthy controls were included in this case-control association study. The number of FOXE1 alanine repeats in each subject was determined by PCR and multiplex fragment analysis by capillary electrophoresis. FOXE1 genotype and allele frequencies among groups were compared by logistic regression and adjusted for sex and age at diagnosis. Data were analysed according to cancer subtype, tumour size and the presence of lymph node or distant metastasis.
RESULTS: FOXE1 alleles with 16 or more alanine repeats were more frequent in patients with tumour size > 1 cm compared to tumour size ≤ 1 cm (adjusted OR 1·44; 95% CI 1·05-1·88; P = 0·019). Genotypes containing at least one allele with 16 or more alanine repeats were associated with larger tumour size (adjusted OR 1·71; 95% CI 1·15-2·57; P = 0·009). No significant differences were observed between cancer subtypes or the presence/absence of metastasis.
CONCLUSIONS: FOXE1 polyalanine repeat polymorphisms are associated with thyroid cancer, but only for tumours larger than 1 cm, suggesting a role in disease progression.

Jendrzejewski J, Liyanarachchi S, Nagy R, et al.
Papillary Thyroid Carcinoma: Association Between Germline DNA Variant Markers and Clinical Parameters.
Thyroid. 2016; 26(9):1276-84 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
BACKGROUND: Papillary thyroid cancer (PTC) is reported to be highly heritable in epidemiological studies. Genome-wide association studies (GWAS) have uncovered several variants associated with PTC predisposition. It remains unknown whether these variants might contribute to better clinical stratification of PTC patients.
METHODS: In order to assess the usefulness of germline genetic analyses in the management of PTC patients, the genotypes of five variants (rs965513, rs944289, rs116909374, rs2439302, and rs966423) were determined in 1216 PTC patients and 1416 controls. Additionally, the expression of seven genes located close to GWAS variants (PTCSC3, MBIP, NKX2-1, FOXE1, DIRC3, PTCSC2, and NRG1) were measured in 73 PTC paired tumor/normal tissues, respectively. Next, the association was analyzed between the genotypes of the germline variants and the levels of gene expression with clinical/pathological features such as age, sex, TNM staging, multifocality status, extrathyroidal expansion, and MACIS score.
RESULTS: The risk allele of rs965513 was associated with larger tumor size (p = 0.025) and extrathyroidal expansion (odd ratio [OR] = 1.29, p = 0.045). The variant rs2439302 showed association with lymph node metastasis (OR = 1.24, p = 0.016), and multifocality status of the tumor (OR = 1.24, p = 0.012). The expression of MBIP was associated with T stage (p = 0.010). MBIP and PTCSC3 displayed lower expression in PTC tissue in males than in females (p = 0.025 and p = 0.036, respectively). NKX2-1 displayed lower expression in patients with N1 stage (p = 0.040).
CONCLUSIONS: The studied germline risk alleles predisposing to PTC were associated with a more aggressive course of the disease reflected by larger tumor diameter, higher multifocality rate, and more advanced N stage at the time of diagnosis. These results show that germline variants not only predispose to PTC but also might impact its clinical course. However, these associations were only moderate, and further large multi-ethnic studies are required to evaluate the usefulness of these germline variants in the clinical stratification of PTC patients.

Sugimachi K, Matsumura T, Shimamura T, et al.
Aberrant Methylation of FOXE1 Contributes to a Poor Prognosis for Patients with Colorectal Cancer.
Ann Surg Oncol. 2016; 23(12):3948-3955 [PubMed] Related Publications
BACKGROUND: Hypermethylation of DNA silences gene expression and is an important event in colorectal cancer (CRC). This study aimed to identify aberrantly methylated genes that contribute to a poor prognosis for patients with CRC.
METHODS: The study comprehensively explored DNA methylation microarray profiles from 396 CRC samples and 45 normal control samples in a database and selected aberrantly methylated transcription factors associated with prognosis and metastasis. Using quantitative reverse transcription polymerase chain reaction, the identified genes in 140 patients with CRC were validated to assess the relationship between expression of methylated genes and prognosis.
RESULTS: In the study, FOXE1 was newly identified as a gene associated with prognosis and metastasis in CRC. Expression of FOXE1 in CRC tissues was significantly lower than in normal colorectal tissues (p = 0.01). The survival rate for the patients with low expression of FOXE1 was significantly lower than that for patients with high expression of FOXE1 in uni- and multivariate analyses. Inhibition of DNA methylation recovered FOXE1 expression in CRC cells.
CONCLUSIONS: Methylation-mediated silencing of FOXE1 expression was shown to be a potential prognostic factor in CRC.

Sigurdson AJ, Brenner AV, Roach JA, et al.
Selected single-nucleotide polymorphisms in FOXE1, SERPINA5, FTO, EVPL, TICAM1 and SCARB1 are associated with papillary and follicular thyroid cancer risk: replication study in a German population.
Carcinogenesis. 2016; 37(7):677-684 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
Several single-nucleotide polymorphisms (SNPs) have been associated with papillary and follicular thyroid cancer (PTC and FTC, respectively) risk, but few have replicated. After analyzing 17525 tag SNPs in 1129 candidate genes, we found associations with PTC risk in SERPINA5, FTO, HEMGN (near FOXE1) and other genes. Here, we report results from a replication effort in a large independent PTC/FTC case-control study conducted in Germany. We evaluated the best tagging SNPs from our previous PTC study and additionally included SNPs in or near FOXE1 and NKX2-1 genes, known susceptibility loci for thyroid cancer. We genotyped 422 PTC and 130 FTC cases and 752 controls recruited from three German clinical centers. We used polytomous logistic regression to simultaneously estimate PTC and FTC associations for 79 SNPs based on log-additive models. We assessed effect modification by body mass index (BMI), gender and age for all SNPs, and selected SNP by SNP interactions. We confirmed associations with PTC and SNPs in FOXE1/HEMGN, SERPINA5 (rs2069974), FTO (rs8047395), EVPL (rs2071194), TICAM1 (rs8120) and SCARB1 (rs11057820) genes. We found associations with SNPs in FOXE1, SERPINA5, FTO, TICAM1 and HSPA6 and FTC. We found two significant interactions between FTO (rs8047395) and BMI (P = 0.0321) and between TICAM1 (rs8120) and FOXE1 (rs10984377) (P = 0.0006). Besides the known associations with FOXE1 SNPs, we confirmed additional PTC SNP associations reported previously. We also found several new associations with FTC risk and noteworthy interactions. We conclude that multiple variants and host factors might interact in complex ways to increase risk of PTC and FTC.

Wang F, Yan D, Ji X, et al.
rs965513 polymorphism as a common risk marker is associated with papillary thyroid cancer.
Oncotarget. 2016; 7(27):41336-41345 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
Papillary thyroid cancer (PTC) is the most common type of thyroid cancer. With the rapid development of genome-wide association studies (GWAS), many genome variants associated with susceptibility to PTC have been identified, including the single nucleotide polymorphism rs965513 (9q22.33) near FOXE1. To evaluate the association between rs965513 and PTC in different ethnicities and countries, we conducted a meta-analysis using relatively large-scale samples from 23 studies (N = 163,136; 20,736 cases and 142,400 controls) by searching the PubMed and Google Scholar databases. Significant heterogeneity caused by different populations among the selected studies was observed. The A allele of rs965513 polymorphism was shown to be highly associated with risk of thyroid cancer, with odds ratios of 1.58 (95% CI 1.32-1.90) in all populations, 1.65 (95% CI 1.31-2.07)) in Caucasian populations and 1.49 in Asian populations. Compared to the dominant and recessive models, we observed the highest odds ratio (OR = 2.80, 95% CI 2.12-3.69) in the homozygous model. These results revealed that the rs965513 polymorphism is a risk factor for thyroid cancer.

Somuncu E, Karatas A, Ferahman S, et al.
The investigation of foxe1 variations in papillary thyroid carcinoma.
Int J Clin Exp Pathol. 2015; 8(10):13458-64 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
BACKGROUND: Recent reports indicated that incidence of thyroid carcinoma is increasing throughout the worldwide. The aim of our study was to determine a possible relationship between Forkhead box E1 (FOXE1) gene variants and histopathological features of papillary thyroid carcinoma.
METHODS: FOXE1 gene variations; rs894673, rs1867277 and rs3758249 were analyzed in 57 Papillary thyroid carcinoma patients and 51 age matched healthy control subjects. Restriction fragment length polymorphism (RFLP) technique was used to specifically detect the variations.
RESULTS: There was a significant difference in the distribution of rs894673 genotypes in Papillary thyroid carcinoma cases (P=0.01). AA genotype presence of rs1867277 was more significantly associated with several histopathological parameters such as focal and diffuse capsular invasion, lymphatic invasion, P3 with P4 tumor grade and surgical margins. AA genotype presence in rs1867277 variation was significantly associated with the classical variant which is subtype of papillary thyroid carcinoma. Furthermore, the presence of the allel A was found to be related with lymph node invasion risk by 2.46 fold, capsular invasion risk by 2.97 fold, and pT3 with pT4 pathological stage risk by 4.13 fold and the presence of allele A in rs1867277 was significantly associated with classic variants. The presence of allele A in rs1867277 was more significantly associated with several histopathological parameters in classic variant in papillary thyroid carcinoma cases such as, the presence of the A allele was found relationship with lymph node invasion risk by 2.0 fold, capsular invasion risk by 2.39 fold , and pT3 with pT4 pathological stage risk by 3.57 fold. In addition, AATT, AAAA and GATT haplotypes (rs1867277 and rs894673) were evaluated for association with papillary thyroid carcinoma cases. Our results indicate that the significant difference according to two-allele haplotype distribution between papillary thyroid carcinoma cases and control groups.
CONCLUSION: Our findings suggest that FOXE1 variations generate a higher risk for poor histopathological features of papillary thyroid carcinoma.

Batista FA, Ward LS, Marcello MA, et al.
Gene expression of thyroid-specific transcription factors may help diagnose thyroid lesions but are not determinants of tumor progression.
J Endocrinol Invest. 2016; 39(4):423-9 [PubMed] Related Publications
PURPOSE: The role of thyroid-specific transcription factors in thyroid malignancy is still poorly understood, so we investigate thyroid-specific transcription factors gene expression both in benign and in malignant thyroid nodules, aiming to study a possible clinical utility of these molecules.
METHODS: We quantified TTF-1, FOXE1 and PAX8 mRNA levels, relating their expression to diagnostic and prognostic features of thyroid tumors. RNA was extracted from 4 normal thyroid tissues, 101 malignant [99 papillary thyroid carcinomas (PTC) and 2 anaplastic thyroid carcinomas] and 99 benign thyroid lesion tissues [49 goiter and 50 follicular adenomas (FA)].
RESULTS: Levels of mRNA of both FOXE1 (P < 0.0001) and PAX8 (P < 0.0001) genes, but not TTF-1 (P = 0.7056), were higher in benign than in malignant thyroid lesions. FOXE1 was able to identify malignant nodules with 75.8 % sensitivity, 76.1 % specificity, 75.8 % positive predictive value, 76.1 % negative predictive value and 75.9 % accuracy. PAX8 was able to identify malignancy with 60.6 % sensitivity, 81.1 % specificity, 76.9 % positive predictive value, 66.4 % negative predictive value and 70.6 % accuracy. Both FOXE1 and PAX8 gene expression patterns were also able to differentiate FA from the follicular variant of PTC-FVPTC. However, the investigated gene expression was neither associated with any clinical feature of tumor aggressiveness nor associated with recurrence or survival.
CONCLUSIONS: We suggest that FOXE1 and PAX8 gene expression patterns may help to diagnose thyroid nodules, identifying malignancy and characterizing follicular-patterned thyroid lesions, but are not determinants of thyroid tumor progression.

Gao Y, Chen F, Niu S, et al.
Replication and Meta-Analysis of Common Gene Mutations in TTF1 and TTF2 with Papillary Thyroid Cancer.
Medicine (Baltimore). 2015; 94(36):e1246 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
Papillary thyroid cancer (PTC), one of the most common malignant thyroid tumors, exits widely in the thyroid of adolescents. Thyroid transcription factor 1 (TTF1) and 2 (TTF2) were thyroid-specific transcription factors, and regulated expression of the thyroid-specific genes. Hence, the aim of the present study was to evaluate the correlation between gene variants of TTF1 and TTF2 and the risk of PTC in Chinese population.Two tagging single-nucleotide polymorphisms (tSNPs) on TTF1 and TTF2 were selected and genotyped by matrix-assisted laser desorption/ionization time-of-flight (MALDITOF) mass spectrometry in a hospital-based case-control study of 297 PTC patients and 594 healthy controls. Furthermore, a meta-analysis of the association between TTF1 and TTF2 and PTC risk was also performed.We found that the rs944289 on the TTF1 was significantly associated with increased PTC risk (TT vs CC, OR = 1.53, 95% CI = 1.05-2.24; CT + TT vs TT, OR = 1.34, 95% CI = 1.00-1.79; T vs C, OR = 1.27, 95% CI = 1.04-1.55). Similarly, the rs965513 on the TTF2 can also elevate the risk of PTC significantly (GA vs GG, OR = 1.67, 95% CI = 1.07-2.59; AA+GA vs AA, OR = 1.37, 95% CI = 1.09-1.82; A vs G, OR = 1.29, 95% CI = 1.05-1.59). Furthermore, results of stratified analysis revealed that the risk effects of rs944289 and rs965513 were more overpowering in the subgroups of patients with MNG, as well as subjects without metastasis. Results of meta-analysis from the previous study and our new data indicated that variants of rs944289 and rs965513 might be the genetic susceptible factors both in Asians and Caucasians.We get the conclusion that mutations of TTF1 and TTF2 are significantly associated with an increasing risk of PTC in Chinese. However, more detailed investigations and further large-scale studies on genetic functions to provide more conclusive and accurate evidence are required in the future.

Jang S, Yu XM, Odorico S, et al.
Novel analogs targeting histone deacetylase suppress aggressive thyroid cancer cell growth and induce re-differentiation.
Cancer Gene Ther. 2015; 22(8):410-6 [PubMed] Related Publications
To develop novel therapies for aggressive thyroid cancers, we have synthesized a collection of histone deacetylase (HDAC) inhibitor analogs named AB1 to AB13, which have different linkers between a metal chelating group and a hydrophobic cap. The purpose of this study was to screen out the most effective compounds and evaluate the therapeutic efficacy. AB2, AB3 and AB10 demonstrated the lowest half-maximal inhibitory concentration (IC50) values in one metastatic follicular and two anaplastic thyroid cancer cell lines. Treatment with each of the three ABs resulted in an increase in apoptosis markers, including cleaved poly adenosine diphosphate ribose polymerase (PARP) and cleaved caspase 3. Additionally, the expression of cell-cycle regulatory proteins p21(WAF1) and p27(Kip1) increased with the treatment of ABs while cyclin D1 decreased. Furthermore, AB2, AB3 and AB10 were able to induce thyrocyte-specific genes in the three thyroid cancer cell lines indicated by increased expression levels of sodium iodide symporter, paired box gene 8, thyroid transcription factor 1 (TTF1), TTF2 and thyroid-stimulating hormone receptors. AB2, AB3 and AB10 suppress thyroid cancer cell growth via cell-cycle arrest and apoptosis. They also induce cell re-differentiation, which could make aggressive cancer cells more susceptible to radioactive iodine therapy.

Geng P, Ou J, Li J, et al.
TITF1 and TITF2 loci variants indicate significant associations with thyroid cancer.
Endocrine. 2015; 50(3):598-607 [PubMed] Related Publications
A number of studies have investigated the influence of TITF1 and TITF2 genetic variants on thyroid carcinogenesis, but their associations remain unclear due to the controversial results. The objective of this study was to test the hypothesis that TITF1 and TITF2 variants modulate thyroid cancer susceptibility. Eligible studies were identified through online searches supplemented by manual search. Either the DerSimonian and Laird method or the Mantel-Haenszel method was used to estimate the risk of thyroid cancer (ORs and 95 % CIs). The pooled ORs were calculated assuming the allele model. We identified a total of 10 publications concerning the topic of interest. Overall, meta-analysis of rs944289 showed 1.11-fold increased risk of thyroid cancer related to the risk T allele (T vs. C: OR 1.11, 95 % CI 1.05-1.17). For rs965513, individuals carrying the risk A allele, compared to individuals with the G allele, had 31 % higher risk of thyroid cancer (A vs. G: OR 1.31, 95 % CI 1.17-1.46). Analyses in total samples for rs1867277, rs1443434, and rs907580 yielded similar associations (A vs. G: OR 1.22, 95 % CI 1.06-1.39; G vs. T: OR 1.26, 95 % CI 1.09-1.45; T vs. C: OR 1.42, 95 % CI 1.21-1.66, respectively). The significant association persisted among Caucasians in subgroup analyses for rs944289 and rs965513. The genetic susceptibility of thyroid cancer seems likely to be associated with the risk allele at rs944289 in the TITF1 gene and at rs1867277, rs965513, rs1443434, and rs907580 in the TITF2 gene.

Xu Y, Chang R, Peng Z, et al.
Loss of polarity protein AF6 promotes pancreatic cancer metastasis by inducing Snail expression.
Nat Commun. 2015; 6:7184 [PubMed] Related Publications
Pancreatic cancer (PC) is a particularly lethal form of cancer with high potential for metastasis to distant organs. Disruption of cell polarity is a hallmark of advanced epithelial tumours. Here we show that the polarity protein AF6 (afadin and MLLT4) is expressed at low levels in PC. We demonstrate that depletion of AF6 markedly promotes proliferation and metastasis of PC cells through upregulation of the expression of Snail protein, and this requires the nuclear localization of AF6. Furthermore, AF6 deficiency in PC cells leads to increased formation of a Dishevelled 2 (Dvl2)-FOXE1 complex on the promoter region of Snail gene, and activation of Snail expression. Altogether, our data established AF6 as a potential inhibitor of metastasis in PC cells. Targeting the Dvl2-FOXE1-Snail signalling axis may thus represent a promising therapeutic strategy.

Mond M, Bullock M, Yao Y, et al.
Somatic Mutations of FOXE1 in Papillary Thyroid Cancer.
Thyroid. 2015; 25(8):904-10 [PubMed] Related Publications
BACKGROUND: Population-based studies have demonstrated an association of single nucleotide polymorphisms close to the thyroid transcription factor forkhead box E1 (FOXE1) gene with thyroid cancer. The dysregulation of forkhead proteins is increasingly recognized to play a role in the development and progression of cancer. The objective of the study was to seek to identify novel mutations in FOXE1 in papillary thyroid cancer (PTC) and to assess the effect of these mutations on protein expression and transcriptional function on FOXE1 responsive promoters.
METHODS: The study was conducted at two tertiary referral hospitals. The coding region of FOXE1 was sequenced in tissue-derived DNA or RNA from 120 patients with PTC and 110 patients with multinodular goiter (MNG). In vitro studies were performed to examine the protein expression and transcriptional function of FOXE1 mutants. A molecular model of the forkhead domain (FHD) of FOXE1 was generated using the SWISS-MODEL online server with the three-dimensional structure of FOXD3 as a template.
RESULTS: Three somatic missense mutations were detected in PTC resulting in the amino acid substitutions P54Q, K95Q, and L112F. One additional mutation was detected in a MNG (G140R). In vitro studies demonstrated marked impairment in transcriptional activation by all four FOXE1 mutants, which was not explained by differences in protein expression. Molecular modeling localized three of the mutations to highly conserved regions of the FHD.
CONCLUSIONS: We have identified novel somatic mutations of FOXE1 in PTC. Mutational inactivation of FOXE1 is an uncommon event in thyroid tumors but may contribute to thyroid carcinogenesis and dedifferentiation in concert with other oncogenic drivers.

He H, Li W, Liyanarachchi S, et al.
Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer.
Proc Natl Acad Sci U S A. 2015; 112(19):6128-33 [PubMed] Article available free on PMC after 15/11/2019 Related Publications
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 fine-mapped 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.

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