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
2011 Impact Factor: 13.757
2011 SCImago Journal Rankings: 1.444
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 Field
Value
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.grantSplicing variant profiling in relation to Estrogen Receptor gene expression in Chinese breast cancer
dc.description.grantThyroid transcription factor-1 (TTF-1), a potential susceptibility gene for familial papillary thyroid carcinoma
dc.description.grantcode96877
dc.description.grantcode98627
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.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
2011 Impact Factor: 13.757
2011 SCImago Journal Rankings: 1.444
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.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
Author Affiliations
  1. Baylor College of Medicine
  2. The University of Hong Kong