title: Telomere shortening and telomerase reverse transcriptase expression in preinvasive bronchial lesions.
abstract: OBJECTIVE
  Telomerase, a ribonucleoprotein complex whose activity is related to the expression of its catalytic subunit human telomerase reverse transcriptase (hTERT), restores telomere length in tumor cells and enables immortality after p53/Rb inactivation has been achieved. To determine the timing of hTERT derepression during bronchial carcinogenesis and its relationship with telomere shortening and the p53/Rb pathway alterations, we did an immunohistochemical and in situ hybridization study in preinvasive and invasive bronchial lesions.
  
  
  METHODS
  hTERT, P53, P16, cyclin D1, Bax-to-Bcl2 ratio, and Ki67 immunostainings were done in 106 preneoplastic lesions and in paired lung carcinoma and normal bronchial mucosae. Concomitantly, hTERT mRNA levels and qualitative telomere shortening were assessed by in situ hybridization and fluorescence in situ hybridization, respectively, in a subset of preneoplastic and neoplastic lesions.
  
  
  RESULTS
  Telomerase was increasingly expressed from normal epithelium to squamous metaplasia, dysplasia, and carcinoma in situ, and decreased in invasive carcinoma (P < 0.0001), with a direct correlation between protein and mRNA levels of expression (P < 0.0001). hTERT expression was directly correlated with P53, Ki67, and Bcl2-to-Bax ratio, suggesting a coupling between telomerase reactivation, proliferation, and resistance to apoptosis. Telomere signals significantly decreased as early as squamous metaplasia and progressively increased over the spectrum of preneoplastic lesions.
  
  
  CONCLUSIONS
  Telomere shortening represents an early genetic abnormality in bronchial carcinogenesis, preceding telomerase expression and p53/Rb inactivation, which predominate in high-grade preinvasive lesions.
authors.affiliation: Department of Pathology, Centre Hospitalier Universitaire Albert Michallon, 38043 Grenoble Cedex 9, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lantuejoul
authors.forename: Jean Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: Luc
authors.initials: L
authors.lastname: Morat
authors.forename: Philippe
authors.initials: P
authors.lastname: Lorimier
authors.forename: Denis
authors.initials: D
authors.lastname: Moro-Sibilot
authors.forename: Laure
authors.initials: L
authors.lastname: Sabatier
authors.forename: Christian
authors.initials: C
authors.lastname: Brambilla
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis; D002277:Carcinoma / Q000235:genetics* / Q000503:physiopathology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000503:physiopathology*; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008175:Lung Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D011230:Precancerous Conditions; D012333:RNA, Messenger / Q000096:biosynthesis; D015398:Signal Transduction; D019098:Telomerase / Q000096:biosynthesis* / Q000494:pharmacology; D016615:Telomere / Q000648:ultrastructure*
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D019098:Telomerase