Telomerase variant A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal carcinomas

Yuwei Zhang, Rodrigo Calado, Mahadev Rao, Julie A. Hong, Alan Keith Meeker, Bogdan Dumitriu, Scott Atay, Peter J. McCormick, Susan H. Garfield, Danny Wangsa, Hesed M. Padilla-Nash, Sandra Burkett, Mary Zhang, Tricia F. Kunst, Nathan R. Peterson, Sichuan Xi, Suzanne Inchauste, Nasser K. Altorki, Alan G. Casson, David G. Beer & 4 others Curtis C. Harris, Thomas Ried, Neal S. Young, David S. Schrump

Research output: Contribution to journalArticle

Abstract

Background: Although implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas. Methods: Sequencing techniques were used to evaluate mutational status of telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) in neoplastic and adjacent normal mucosa from 143 esophageal cancer (EsC) patients. MTS, flow cytometry, time lapse microscopy, and murine xenograft techniques were used to assess proliferation, apoptosis, chemotaxis, and tumorigenicity of EsC cells expressing either wtTERT or TERT variants. Immunoprecipitation, immunoblot, immunofluorescence, promoter-reporter and qRT-PCR techniques were used to evaluate interactions of TERT and several TERT variants with BRG-1 and β-catenin, and to assess expression of cytoskeletal proteins, and cell signaling. Fluorescence in-situ hybridization and spectral karyotyping techniques were used to examine telomere length and chromosomal stability. Results: Sequencing analysis revealed one deletion involving TERC (TERC del 341-360), and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous); A1062T (4 heterozygous)]. The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p

Original languageEnglish (US)
Article numbere101010
JournalPLoS One
Volume9
Issue number7
DOIs
StatePublished - Jul 1 2014

Fingerprint

telomerase
Telomerase
telomeres
Telomere
carcinoma
Carcinoma
RNA-directed DNA polymerase
Esophageal Neoplasms
esophageal neoplasms
Spectral Karyotyping
RNA
Cell signaling
Catenins
Chromosomal Instability
Mutation
Cytoskeletal Proteins
Flow cytometry
Hematologic Neoplasms
Chemotaxis
Blood Donors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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Telomerase variant A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal carcinomas. / Zhang, Yuwei; Calado, Rodrigo; Rao, Mahadev; Hong, Julie A.; Meeker, Alan Keith; Dumitriu, Bogdan; Atay, Scott; McCormick, Peter J.; Garfield, Susan H.; Wangsa, Danny; Padilla-Nash, Hesed M.; Burkett, Sandra; Zhang, Mary; Kunst, Tricia F.; Peterson, Nathan R.; Xi, Sichuan; Inchauste, Suzanne; Altorki, Nasser K.; Casson, Alan G.; Beer, David G.; Harris, Curtis C.; Ried, Thomas; Young, Neal S.; Schrump, David S.

In: PLoS One, Vol. 9, No. 7, e101010, 01.07.2014.

Research output: Contribution to journalArticle

Zhang, Y, Calado, R, Rao, M, Hong, JA, Meeker, AK, Dumitriu, B, Atay, S, McCormick, PJ, Garfield, SH, Wangsa, D, Padilla-Nash, HM, Burkett, S, Zhang, M, Kunst, TF, Peterson, NR, Xi, S, Inchauste, S, Altorki, NK, Casson, AG, Beer, DG, Harris, CC, Ried, T, Young, NS & Schrump, DS 2014, 'Telomerase variant A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal carcinomas', PLoS One, vol. 9, no. 7, e101010. https://doi.org/10.1371/journal.pone.0101010
Zhang, Yuwei ; Calado, Rodrigo ; Rao, Mahadev ; Hong, Julie A. ; Meeker, Alan Keith ; Dumitriu, Bogdan ; Atay, Scott ; McCormick, Peter J. ; Garfield, Susan H. ; Wangsa, Danny ; Padilla-Nash, Hesed M. ; Burkett, Sandra ; Zhang, Mary ; Kunst, Tricia F. ; Peterson, Nathan R. ; Xi, Sichuan ; Inchauste, Suzanne ; Altorki, Nasser K. ; Casson, Alan G. ; Beer, David G. ; Harris, Curtis C. ; Ried, Thomas ; Young, Neal S. ; Schrump, David S. / Telomerase variant A279T induces telomere dysfunction and inhibits non-canonical telomerase activity in esophageal carcinomas. In: PLoS One. 2014 ; Vol. 9, No. 7.
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AU - Zhang, Yuwei

AU - Calado, Rodrigo

AU - Rao, Mahadev

AU - Hong, Julie A.

AU - Meeker, Alan Keith

AU - Dumitriu, Bogdan

AU - Atay, Scott

AU - McCormick, Peter J.

AU - Garfield, Susan H.

AU - Wangsa, Danny

AU - Padilla-Nash, Hesed M.

AU - Burkett, Sandra

AU - Zhang, Mary

AU - Kunst, Tricia F.

AU - Peterson, Nathan R.

AU - Xi, Sichuan

AU - Inchauste, Suzanne

AU - Altorki, Nasser K.

AU - Casson, Alan G.

AU - Beer, David G.

AU - Harris, Curtis C.

AU - Ried, Thomas

AU - Young, Neal S.

AU - Schrump, David S.

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N2 - Background: Although implicated in the pathogenesis of several chronic inflammatory disorders and hematologic malignancies, telomerase mutations have not been thoroughly characterized in human cancers. The present study was performed to examine the frequency and potential clinical relevance of telomerase mutations in esophageal carcinomas. Methods: Sequencing techniques were used to evaluate mutational status of telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC) in neoplastic and adjacent normal mucosa from 143 esophageal cancer (EsC) patients. MTS, flow cytometry, time lapse microscopy, and murine xenograft techniques were used to assess proliferation, apoptosis, chemotaxis, and tumorigenicity of EsC cells expressing either wtTERT or TERT variants. Immunoprecipitation, immunoblot, immunofluorescence, promoter-reporter and qRT-PCR techniques were used to evaluate interactions of TERT and several TERT variants with BRG-1 and β-catenin, and to assess expression of cytoskeletal proteins, and cell signaling. Fluorescence in-situ hybridization and spectral karyotyping techniques were used to examine telomere length and chromosomal stability. Results: Sequencing analysis revealed one deletion involving TERC (TERC del 341-360), and two non-synonymous TERT variants [A279T (2 homozygous, 9 heterozygous); A1062T (4 heterozygous)]. The minor allele frequency of the A279T variant was five-fold higher in EsC patients compared to healthy blood donors (p

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