Association of FOXE1 Polyalanine Repeat Region with Papillary Thyroid Cancer

Bullock, Martyn, Duncan, Emma L., O'Neill, Christine, Tacon, Lyndal, Sywak, Mark, Sidhu, Stan, Delbridge, Leigh, Learoyd, Diana, Robinson, Bruce G., Ludgate, Marian, & Clifton-Bligh, Roderick J. (2012) Association of FOXE1 Polyalanine Repeat Region with Papillary Thyroid Cancer. Journal of Clinical Endocrinology and Metabolism, 97(9), E1814-E1819.

View at publisher



Polyalanine tract variations in transcription factors have been identified for a wide spectrum of developmental disorders. The thyroid transcription factor forkhead factor E1 (FOXE1) contains a polymorphic polyalanine tract with 12-22 alanines. Single-nucleotide polymorphisms (SNP) close to this locus are associated with papillary thyroid cancer (PTC), and a strong linkage disequilibrium block extends across this region.


The objective of the study was to assess whether the FOXE1 polyalanine repeat region was associated with PTC and to assess the effect of polyalanine repeat region variants on protein expression, DNA binding, and transcriptional function on FOXE1-responsive promoters.


This was a case-control study.


The study was conducted at a tertiary referral hospital.


The FOXE1 polyalanine repeat region and tag SNP were genotyped in 70 PTC, with a replication in a further 92 PTC, and compared with genotypes in 5767 healthy controls (including 5667 samples from the Wellcome Trust Case Control Consortium). In vitro studies were performed to examine the protein expression, DNA binding, and transcriptional function for FOXE1 variants of different polyalanine tract lengths.


All the genotyped SNP were in tight linkage disequilibrium, including the FOXE1 polyalanine repeat region. We confirmed the strong association of rs1867277 with PTC (overall P = 1 × 10(-7), odds ratio 1.84, confidence interval 1.31-2.57). rs1867277 was in tight linkage disequilibrium with the FOXE1 polyalanine repeat region (r(2) = 0.95). FOXE1(16Ala) was associated with PTC with an odds ratio of 2.23 (confidence interval 1.42-3.50; P = 0.0005). Functional studies in vitro showed that FOXE1(16Ala) was transcriptionally impaired compared with FOXE1(14Ala), which was not due to differences in protein expression or DNA binding.


We have confirmed the previous association of FOXE1 with PTC. Our data suggest that the coding polyalanine expansion in FOXE1 may be responsible for the observed association between FOXE1 and PTC.

Impact and interest:

22 citations in Scopus
Search Google Scholar™
21 citations in Web of Science®

Citation counts are sourced monthly from Scopus and Web of Science® citation databases.

These databases contain citations from different subsets of available publications and different time periods and thus the citation count from each is usually different. Some works are not in either database and no count is displayed. Scopus includes citations from articles published in 1996 onwards, and Web of Science® generally from 1980 onwards.

Citations counts from the Google Scholar™ indexing service can be viewed at the linked Google Scholar™ search.

ID Code: 94182
Item Type: Journal Article
Refereed: Yes
Keywords: alanine, forkhead factor E1, genomic DNA, polyalanine, transcription factor, unclassified drug, article, binding affinity, binding site, case control study, controlled study, DNA binding, follow up, forkhead factor E1 gene, gene frequency, gene linkage disequilibrium, gene location, gene replication, genetic association, genetic variability, genotyping technique, human, human tissue, in vitro study, major clinical study, oncogene, priority journal, promoter region, protein expression, sequence analysis, single nucleotide polymorphism, thyroid carcinoma, Adult, Aged, Carcinoma, Papillary, Case-Control Studies, Cohort Studies, DNA, DNA, Complementary, Electrophoretic Mobility Shift Assay, Female, Forkhead Transcription Factors, Gene Expression, Genotype, HEK293 Cells, Humans, Linkage Disequilibrium, Male, Middle Aged, Peptides, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Repetitive Sequences, Nucleic Acid, Thyroid Neoplasms, Transcription, Genetic, Transfection
DOI: 10.1210/jc.2012-1456
ISSN: 1945-7197
Divisions: Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2012 by The Endocrine Society
Deposited On: 29 Mar 2016 05:25
Last Modified: 30 Mar 2016 01:05

Export: EndNote | Dublin Core | BibTeX

Repository Staff Only: item control page