Identification of a novel germline FOXE1 variant in patients with familial non-medullary thyroid carcinoma (FNMTC)

Simões‐Pereira, Joana; Silva, Joana G.; Tomaz, Rute; Pinto, António E.; Bugalho, Maria João; Leite, Valeriano; Cavaco, Branca

doi:10.1007/s12020-014-0470-0

Cited by 64 publications

(57 citation statements)

References 28 publications

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“…This study supports the involvement of a germline FOXE1 variant in FNMTC etiology in these familial cases (Pereira et al 2015).…”

Section: :12supporting

confidence: 86%

“…These include 9 polymorphisms and 1 variant (c.743C>G, p.A248G) that was not previously described. This variant segregated with PTC in one FNMTC family and was also detected in a case of sporadic PTC (Tomaz et al 2012, Pereira et al 2015. FOXE1 polyalanine tract expansions consisting of more than 14 alanine residues were associated with both FNMTC and sporadic NMTC (Tomaz et al 2012).…”

Section: Foxe1mentioning

confidence: 96%

“…The reported susceptibility genes include SRGAP1 (He et al 2013a), TITF-1/NKX2-1 (Ngan et al 2009), FOXE1 (Pereira et al 2015) and telomere-telomerase complex (Capezzone et al 2008a(Capezzone et al , 2011. Chromosomal loci reported to be associated with non-syndromic FNMTC include TCO (19q13.2) (Canzian et al 1998), fPTC/ PRN (1q21) (Malchoff et al 2000), FTEN (8p23.1-p22) (Cavaco et al 2008b), NMTC1 (2q21) (McKay et al 2001), MNG1 (14q32) (Bignell et al 1997), 6q22 ), 8q24 ) and 4q32 (He et al 2013b).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Familial non-medullary thyroid cancer: unraveling the genetic maze

Yang¹,

Ngeow²

2016

Endocrine-Related Cancer

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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 FNMTCassociated 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.

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“…This study supports the involvement of a germline FOXE1 variant in FNMTC etiology in these familial cases (Pereira et al 2015).…”

Section: :12supporting

confidence: 86%

Section: Foxe1mentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Familial non-medullary thyroid cancer: unraveling the genetic maze

Yang¹,

Ngeow²

2016

Endocrine-Related Cancer

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“…Rs965513 is part of a haplotype block that regulates FOXE1 and PTCSC2 expression through long-range enhancer elements (13). A role for FOXE1 in PTC development has been proposed in several studies (14)(15)(16)(17).…”

mentioning

confidence: 99%

Papillary Thyroid Carcinoma: Association Between Germline DNA Variant Markers and Clinical Parameters

Jendrzejewski

Liyanarachchi

Nagy

et al. 2016

Thyroid

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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.

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“…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).…”

mentioning

confidence: 99%

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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Identification of a novel germline FOXE1 variant in patients with familial non-medullary thyroid carcinoma (FNMTC)

Cited by 64 publications

References 28 publications

Familial non-medullary thyroid cancer: unraveling the genetic maze

Familial non-medullary thyroid cancer: unraveling the genetic maze

Papillary Thyroid Carcinoma: Association Between Germline DNA Variant Markers and Clinical Parameters

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

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