Association of FOXE1 polyalanine repeat region with papillary thyroid cancer.
BACKGROUND
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.


OBJECTIVE
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.


METHODS
This was a case-control study.


METHODS
The study was conducted at a tertiary referral hospital.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Cancer Genetics Unit, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia.
Martyn
M
Bullock
Emma L
EL
Duncan
Christine
C
O'Neill
Lyndal
L
Tacon
Mark
M
Sywak
Stan
S
Sidhu
Leigh
L
Delbridge
Diana
D
Learoyd
Bruce G
BG
Robinson
Marian
M
Ludgate
Roderick J
RJ
Clifton-Bligh
D000328:Adult; D000368:Aged; D002291:Carcinoma, Papillary / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D015870:Gene Expression / Q000235:genetics; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D013964:Thyroid Neoplasms / Q000453:epidemiology / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics; D014162:Transfection
D018076:DNA, Complementary; C106894:FOXE1 protein, human; D051858:Forkhead Transcription Factors; D010455:Peptides; C019529:polyalanine; D004247:DNA