Association of <i><scp>FOXE</scp>1</i> polyalanine repeat region with thyroid cancer is dependent on tumour size

Raimundo, Joana; Alvelos, Maria Inês; Azevedo, Teresa; Martins, Teresa; Rodrigues, Fernando; Lemos, Manuel C.

doi:10.1111/cen.13166

Cited by 5 publications

(3 citation statements)

References 22 publications

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“…Clinical parameters (age at diagnosis, gender, tumor subtype, tumor size, presence of lymph node, or distant metastasis) were analyzed to assess if genetic susceptibility was limited to subgroups of patients, which has been reported for other genetic variants [12,25,26]. Our study revealed a decreased frequency of the CYP2R1 rs2060793 (G > A) minor allele in patients with metastatic disease (OR 0.61, 95% CI 0.40–0.93), which suggests a protective effect of this SNP against more advanced disease.…”

Section: Discussionmentioning

confidence: 99%

“…The control group consisted of 500 (113 males and 387 females, mean age ± SD = 35.9 ± 14.2 years) Caucasian Portuguese unrelated volunteers who were recruited among blood donors from the same geographical area. Cases and controls were the same as those used in a previous study showing an association of FOXE1 variants with thyroid cancer [12], with some replacements due to missing DNA samples. The study was approved by the local research ethics committees (Portuguese Institute of Oncology of Coimbra, and Faculty of Health Sciences, University of Beira Interior, Ref: CE-FCS-2012-011).…”

Section: Methodsmentioning

confidence: 99%

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Association of Vitamin D Pathway Genetic Variation and Thyroid Cancer

Carvalho

Gonçalves

Almeida

et al. 2019

Genes

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Vitamin D is mostly known for its role in bone and calcium metabolism. However, studies have suggested that it also has inhibitory effects on tumor development and progression. Genetic variants close to genes that encode crucial enzymes for the synthesis (DHCR7 rs12785878), metabolism (CYP2R1 rs2060793) and degradation (CYP24A1 rs6013897) of vitamin D have been associated with serum levels of vitamin D. The aim of this case-control study was to determine the effect of these variants in the vitamin D pathway on the susceptibility to thyroid cancer. Five hundred patients with differentiated thyroid cancer and 500 controls were genotyped for the DHCR7 rs12785878, CYP2R1 rs2060793, and CYP24A1 rs6013897 variants. Genotype and allele frequencies were compared between patients and controls. The DHCR7 rs12785878 minor allele was associated with thyroid cancer under an additive (OR 1.38, 95% CI 1.15–1.65, p = 0.0004) and codominant (OR 1.88, 95% CI 1.30–2.74, p = 0.0021) model. These findings suggest that DHCR7 polymorphisms may be associated with an increased risk of thyroid cancer due to an effect of this gene on circulating vitamin D levels.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Association of Vitamin D Pathway Genetic Variation and Thyroid Cancer

Carvalho

Gonçalves

Almeida

et al. 2019

Genes

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“…FOXE1 (Forkhead Box E1), a Forkhead (FOX) transcription factor is essential for thyroid gland development [ 3 – 9 ], and is also required in the hormonal regulation of thyroglobulin ( TG ) and thyroid peroxidase ( TPO ) gene expression by the adult thyrocyte [ 10 – 12 ]. Recent genetic studies have identified germline allelic variation in and near FOXE1 to be strongly associated with non-medullary thyroid cancer risk including single nucleotide variants rs965513[A] (56 kb upstream of FOXE1 ) [ 13 – 18 ] and rs1867277[A] (within its promoter) [ 19 – 21 ], and variation within the FOXE1 polyalanine tract [ 22 – 24 ]; resolution of causal variants responsible for the association with thyroid cancer has been difficult due to strong linkage disequilibrium between all three variants. Nevertheless, these allelic variants were associated with altered FOXE1 expression in PTC tissues [ 25 ], whereas complete loss of FOXE1 expression is often found in anaplastic thyroid cancer (ATC) [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Thyroid transcription factor FOXE1 interacts with ETS factor ELK1 to co-regulate TERT

Bullock

Lim

et al. 2016

Oncotarget

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BackgroundAlthough 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.ResultsIn 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.MethodologyWe 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.ConclusionsFOXE1 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.

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