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Article: A germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma
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TitleA germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma
 
AuthorsNgan, ESW
Lang, BHH2
Liu, T2
Shum, CKY2
So, MT2
Lau, DKC2
Leon, TYY2
Cherny, SS2
Tsai, SY1
Lo, CY2
Khoo, US2
Tam, PKH2
GarciaBarceló, MM2
 
Issue Date2009
 
PublisherOxford University Press. The Journal's web site is located at http://jncicancerspectrum.oxfordjournals.org/
 
CitationJournal Of The National Cancer Institute, 2009, v. 101 n. 3, p. 162-175 [How to Cite?]
DOI: http://dx.doi.org/10.1093/jnci/djn471
 
AbstractBackground: The genetic factors that determine the risk of papillary thyroid carcinoma (PTC) among patients with multinodular goiter (MNG) remain undefined. Because thyroid transcription factor-1 (TTF-1) is important to thyroid development, we evaluated whether the gene that encodes it, TITF-1/NKX2.1, is a genetic determinant of MNG/PTC predisposition. Methods: Twenty unrelated PTC patients with a history of MNG (MNG/PTC), 284 PTC patients without a history of MNG (PTC), and 349 healthy control subjects were screened for germline mutation(s) in TITF-1/NKX2.1 by sequencing of amplified DNA from blood. The effects of the mutation on the growth and differentiation of thyroid cells were demonstrated by ectopic expression of wild-type (WT) and mutant proteins in PCCL3 normal rat thyroid cells, followed by tests of cell proliferation, activation of cell growth pathways, and transcription of TTF-1 target genes. All statistical tests were two-sided. Results: A missense mutation (1016C>T) was identified in TITF-1/NKX2.1 that led to a mutant TTF-1 protein (A339V) in four of the 20 MNG/PTC patients (20%). These patients developed substantially more advanced tumors than MNG/PTC or PTC patients without the mutation (P =. 022, Fisher exact test). Notably, this germline mutation was dominantly inherited in two families, with some members bearing the mutation affected with MNG, associated with either PTC or colon cancer. The mutation encoding the A339V substitution was not found among the 349 healthy control subjects nor among the 284 PTC patients who had no history of MNG. Overexpression of A339V TTF-1 in PCCL3 cells, as compared with overexpression of WT TTF-1, was associated with increased cell proliferation including thyrotropin-independent growth (average A339V proliferation rate = 134.27%, WT rate = 104.43%, difference = 34.3%, 95% confidence interval = 12.0% to 47.7%, P =. 010), enhanced STAT3 activation, and impaired transcription of the thyroid-specific genes Tg, TSH-R, and Pax-8. Conclusion: This is the first germline mutation identified in MNG/PTC patients. It could contribute to predisposition for MNG and/or PTC and to the pathogenesis of PTC. © The Author 2009. Published by Oxford University Press. All rights reserved.
 
ISSN0027-8874
2013 Impact Factor: 15.161
2013 SCImago Journal Rankings: 7.066
 
DOIhttp://dx.doi.org/10.1093/jnci/djn471
 
ISI Accession Number IDWOS:000263165100009
Funding AgencyGrant Number
University of Hong KongHKU 772808M
HKU 767307M
Funding Information:

This work was supported by a seed funding grant for basic research from the University of Hong Kong to E. S. W. N., and by research grants HKU 772808M and HKU 767307M from the Hong Kong Research Grants Council to E. S. W. N. and U.- S. K., respectively.

 
ReferencesReferences in Scopus
 
GrantsSplicing variant profiling in relation to Estrogen Receptor gene expression in Chinese breast cancer
Thyroid transcription factor-1 (TTF-1), a potential susceptibility gene for familial papillary thyroid carcinoma
 
DC FieldValue
dc.contributor.authorNgan, ESW
 
dc.contributor.authorLang, BHH
 
dc.contributor.authorLiu, T
 
dc.contributor.authorShum, CKY
 
dc.contributor.authorSo, MT
 
dc.contributor.authorLau, DKC
 
dc.contributor.authorLeon, TYY
 
dc.contributor.authorCherny, SS
 
dc.contributor.authorTsai, SY
 
dc.contributor.authorLo, CY
 
dc.contributor.authorKhoo, US
 
dc.contributor.authorTam, PKH
 
dc.contributor.authorGarciaBarceló, MM
 
dc.date.accessioned2010-05-31T04:14:18Z
 
dc.date.available2010-05-31T04:14:18Z
 
dc.date.issued2009
 
dc.description.abstractBackground: The genetic factors that determine the risk of papillary thyroid carcinoma (PTC) among patients with multinodular goiter (MNG) remain undefined. Because thyroid transcription factor-1 (TTF-1) is important to thyroid development, we evaluated whether the gene that encodes it, TITF-1/NKX2.1, is a genetic determinant of MNG/PTC predisposition. Methods: Twenty unrelated PTC patients with a history of MNG (MNG/PTC), 284 PTC patients without a history of MNG (PTC), and 349 healthy control subjects were screened for germline mutation(s) in TITF-1/NKX2.1 by sequencing of amplified DNA from blood. The effects of the mutation on the growth and differentiation of thyroid cells were demonstrated by ectopic expression of wild-type (WT) and mutant proteins in PCCL3 normal rat thyroid cells, followed by tests of cell proliferation, activation of cell growth pathways, and transcription of TTF-1 target genes. All statistical tests were two-sided. Results: A missense mutation (1016C>T) was identified in TITF-1/NKX2.1 that led to a mutant TTF-1 protein (A339V) in four of the 20 MNG/PTC patients (20%). These patients developed substantially more advanced tumors than MNG/PTC or PTC patients without the mutation (P =. 022, Fisher exact test). Notably, this germline mutation was dominantly inherited in two families, with some members bearing the mutation affected with MNG, associated with either PTC or colon cancer. The mutation encoding the A339V substitution was not found among the 349 healthy control subjects nor among the 284 PTC patients who had no history of MNG. Overexpression of A339V TTF-1 in PCCL3 cells, as compared with overexpression of WT TTF-1, was associated with increased cell proliferation including thyrotropin-independent growth (average A339V proliferation rate = 134.27%, WT rate = 104.43%, difference = 34.3%, 95% confidence interval = 12.0% to 47.7%, P =. 010), enhanced STAT3 activation, and impaired transcription of the thyroid-specific genes Tg, TSH-R, and Pax-8. Conclusion: This is the first germline mutation identified in MNG/PTC patients. It could contribute to predisposition for MNG and/or PTC and to the pathogenesis of PTC. © The Author 2009. Published by Oxford University Press. All rights reserved.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationJournal Of The National Cancer Institute, 2009, v. 101 n. 3, p. 162-175 [How to Cite?]
DOI: http://dx.doi.org/10.1093/jnci/djn471
 
dc.identifier.doihttp://dx.doi.org/10.1093/jnci/djn471
 
dc.identifier.eissn1460-2105
 
dc.identifier.epage175
 
dc.identifier.f10001147418
 
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dc.identifier.f10001147418
 
dc.identifier.f10001147418
 
dc.identifier.f10001147418
 
dc.identifier.f10001147418
 
dc.identifier.f10001147418
 
dc.identifier.hkuros154404
 
dc.identifier.isiWOS:000263165100009
Funding AgencyGrant Number
University of Hong KongHKU 772808M
HKU 767307M
Funding Information:

This work was supported by a seed funding grant for basic research from the University of Hong Kong to E. S. W. N., and by research grants HKU 772808M and HKU 767307M from the Hong Kong Research Grants Council to E. S. W. N. and U.- S. K., respectively.

 
dc.identifier.issn0027-8874
2013 Impact Factor: 15.161
2013 SCImago Journal Rankings: 7.066
 
dc.identifier.issue3
 
dc.identifier.pmid19176457
 
dc.identifier.scopuseid_2-s2.0-59749093841
 
dc.identifier.spage162
 
dc.identifier.urihttp://hdl.handle.net/10722/60590
 
dc.identifier.volume101
 
dc.languageeng
 
dc.publisherOxford University Press. The Journal's web site is located at http://jncicancerspectrum.oxfordjournals.org/
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofJournal of the National Cancer Institute
 
dc.relation.projectSplicing variant profiling in relation to Estrogen Receptor gene expression in Chinese breast cancer
 
dc.relation.projectThyroid transcription factor-1 (TTF-1), a potential susceptibility gene for familial papillary thyroid carcinoma
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshAdolescent
 
dc.subject.meshAdult
 
dc.subject.meshAged
 
dc.subject.meshAged, 80 and over
 
dc.subject.meshAlanine
 
dc.subject.meshAnimals
 
dc.subject.meshCarcinoma, Papillary - genetics - metabolism - pathology
 
dc.subject.meshCase-Control Studies
 
dc.subject.meshCell Proliferation
 
dc.subject.meshCell Transformation, Neoplastic - genetics - metabolism
 
dc.subject.meshChild
 
dc.subject.meshElectrophoretic Mobility Shift Assay
 
dc.subject.meshFemale
 
dc.subject.meshGene Expression Regulation, Neoplastic
 
dc.subject.meshGerm-Line Mutation
 
dc.subject.meshGoiter, Nodular - genetics - metabolism - pathology
 
dc.subject.meshHumans
 
dc.subject.meshImmunoblotting
 
dc.subject.meshLuciferases - diagnostic use
 
dc.subject.meshMale
 
dc.subject.meshMiddle Aged
 
dc.subject.meshNeoplasm Staging
 
dc.subject.meshNuclear Proteins - genetics - metabolism
 
dc.subject.meshRats
 
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction
 
dc.subject.meshSignal Transduction - genetics
 
dc.subject.meshThyroid Gland - cytology - metabolism
 
dc.subject.meshThyroid Neoplasms - genetics - metabolism - pathology
 
dc.subject.meshTranscription Factors - genetics - metabolism
 
dc.subject.meshTranscription, Genetic
 
dc.subject.meshUp-Regulation
 
dc.subject.meshValine
 
dc.subject.meshYoung Adult
 
dc.titleA germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma
 
dc.typeArticle
 
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<contributor.author>Lau, DKC</contributor.author>
<contributor.author>Leon, TYY</contributor.author>
<contributor.author>Cherny, SS</contributor.author>
<contributor.author>Tsai, SY</contributor.author>
<contributor.author>Lo, CY</contributor.author>
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Author Affiliations
  1. Baylor College of Medicine
  2. The University of Hong Kong