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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

TitleA germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinoma
Authors
Issue Date2009
PublisherOxford University Press. The Journal's web site is located at http://jncicancerspectrum.oxfordjournals.org/
Citation
Journal Of The National Cancer Institute, 2009, v. 101 n. 3, p. 162-175 How to Cite?
Abstract
Background: 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.
Persistent Identifierhttp://hdl.handle.net/10722/60590
ISSN
2013 Impact Factor: 15.161
2013 SCImago Journal Rankings: 7.066
ISI Accession Number ID
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.

References
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DC FieldValueLanguage
dc.contributor.authorNgan, ESWen_HK
dc.contributor.authorLang, BHHen_HK
dc.contributor.authorLiu, Ten_HK
dc.contributor.authorShum, CKYen_HK
dc.contributor.authorSo, MTen_HK
dc.contributor.authorLau, DKCen_HK
dc.contributor.authorLeon, TYYen_HK
dc.contributor.authorCherny, SSen_HK
dc.contributor.authorTsai, SYen_HK
dc.contributor.authorLo, CYen_HK
dc.contributor.authorKhoo, USen_HK
dc.contributor.authorTam, PKHen_HK
dc.contributor.authorGarciaBarceló, MMen_HK
dc.date.accessioned2010-05-31T04:14:18Z-
dc.date.available2010-05-31T04:14:18Z-
dc.date.issued2009en_HK
dc.identifier.citationJournal Of The National Cancer Institute, 2009, v. 101 n. 3, p. 162-175en_HK
dc.identifier.issn0027-8874en_HK
dc.identifier.urihttp://hdl.handle.net/10722/60590-
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.en_HK
dc.languageengen_HK
dc.publisherOxford University Press. The Journal's web site is located at http://jncicancerspectrum.oxfordjournals.org/en_HK
dc.relation.ispartofJournal of the National Cancer Instituteen_HK
dc.subject.meshAdolescenten_HK
dc.subject.meshAdulten_HK
dc.subject.meshAgeden_HK
dc.subject.meshAged, 80 and overen_HK
dc.subject.meshAlanineen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshCarcinoma, Papillary - genetics - metabolism - pathologyen_HK
dc.subject.meshCase-Control Studiesen_HK
dc.subject.meshCell Proliferationen_HK
dc.subject.meshCell Transformation, Neoplastic - genetics - metabolismen_HK
dc.subject.meshChilden_HK
dc.subject.meshElectrophoretic Mobility Shift Assayen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshGene Expression Regulation, Neoplasticen_HK
dc.subject.meshGerm-Line Mutationen_HK
dc.subject.meshGoiter, Nodular - genetics - metabolism - pathologyen_HK
dc.subject.meshHumansen_HK
dc.subject.meshImmunoblottingen_HK
dc.subject.meshLuciferases - diagnostic useen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMiddle Ageden_HK
dc.subject.meshNeoplasm Stagingen_HK
dc.subject.meshNuclear Proteins - genetics - metabolismen_HK
dc.subject.meshRatsen_HK
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen_HK
dc.subject.meshSignal Transduction - geneticsen_HK
dc.subject.meshThyroid Gland - cytology - metabolismen_HK
dc.subject.meshThyroid Neoplasms - genetics - metabolism - pathologyen_HK
dc.subject.meshTranscription Factors - genetics - metabolismen_HK
dc.subject.meshTranscription, Geneticen_HK
dc.subject.meshUp-Regulationen_HK
dc.subject.meshValineen_HK
dc.subject.meshYoung Adulten_HK
dc.titleA germline mutation (A339V) in thyroid transcription factor-1 (TITF-1/NKX2.1) in patients with multinodular goiter and papillary thyroid carcinomaen_HK
dc.typeArticleen_HK
dc.identifier.emailNgan, ESW: engan@hkucc.hku.hken_HK
dc.identifier.emailCherny, SS: cherny@hku.hken_HK
dc.identifier.emailKhoo, US: uskhoo@hkucc.hku.hken_HK
dc.identifier.emailTam, PKH: paultam@hkucc.hku.hken_HK
dc.identifier.emailGarciaBarceló, MM: mmgarcia@hkucc.hku.hken_HK
dc.identifier.authorityNgan, ESW=rp00422en_HK
dc.identifier.authorityCherny, SS=rp00232en_HK
dc.identifier.authorityKhoo, US=rp00362en_HK
dc.identifier.authorityTam, PKH=rp00060en_HK
dc.identifier.authorityGarciaBarceló, MM=rp00445en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1093/jnci/djn471en_HK
dc.identifier.pmid19176457en_HK
dc.identifier.scopuseid_2-s2.0-59749093841en_HK
dc.identifier.hkuros154404en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-59749093841&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume101en_HK
dc.identifier.issue3en_HK
dc.identifier.spage162en_HK
dc.identifier.epage175en_HK
dc.identifier.eissn1460-2105-
dc.identifier.isiWOS:000263165100009-
dc.publisher.placeUnited Kingdomen_HK
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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.identifier.scopusauthoridNgan, ESW=22234827500en_HK
dc.identifier.scopusauthoridLang, BHH=7201907327en_HK
dc.identifier.scopusauthoridLiu, T=9273613400en_HK
dc.identifier.scopusauthoridShum, CKY=35286215500en_HK
dc.identifier.scopusauthoridSo, MT=8748542200en_HK
dc.identifier.scopusauthoridLau, DKC=10642145100en_HK
dc.identifier.scopusauthoridLeon, TYY=10641704600en_HK
dc.identifier.scopusauthoridCherny, SS=7004670001en_HK
dc.identifier.scopusauthoridTsai, SY=7403478781en_HK
dc.identifier.scopusauthoridLo, CY=16417392800en_HK
dc.identifier.scopusauthoridKhoo, US=7004195799en_HK
dc.identifier.scopusauthoridTam, PKH=7202539421en_HK
dc.identifier.scopusauthoridGarciaBarceló, MM=6701767303en_HK

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