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Telomere Shortening and Telomerase Reverse Transcriptase Expression in Preinvasive Bronchial Lesions

¹ Department of Pathology, Centre Hospitalier Universitaire Albert Michallon; ² Lung Cancer Research Group, Institut National de la Sante et de la Recherche Medicale Unit 578, Institut Albert Bonniot, Grenoble, France; and ³ Radiobiology and Oncology Laboratory, Direction des Sciences du Vivant, Departement de Radiobiologie et Radiopathologie, Commissariat al'Energie Atomique, Fontenay aux Roses, France

Requests for reprints: Elisabeth Brambilla, Department of Pathology, Centre Hospitalier Universitaire Albert Michallon, BP 217, Cedex 9, 38043 Grenoble, France. Phone: 33-476-765-486; Fax: 33-476-765-949; E mail: EBrambilla{at}chu-grenoble.fr.

Purpose: 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.

Experimental Design: 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.

Key Words: lung cancer • preneoplastic lesion • hTERT • immunohistochemistry • in situ hybridization • FISH • telomere length

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