Telomere Shortening and Telomerase Reverse Transcriptase Expression in Preinvasive Bronchial Lesions

Abstract

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, Baxto-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.

Severe dysplasia can be distinguished from moderate and mild dysplasia of bronchial mucosa by changes in Ki-67 index

“…There were no significant differences in nuclear size between various grades of dysplasia (mild, moderate and severe), as well as between invasive carcinoma and CIS. The uncertainty in classification of the intermediate grades of dysplasia by visual examination, overlap between categories and our karyometric results support some investigators and clinicians who use only two divisions -low-grade versus high-grade dysplasia [16][17][18][19][20][21]. On the other hand, according to our results, the Ki-67 index was significantly higher in severe dysplasia than in mild and moderate dysplasias (p < 0.01).…”

Novel automated three‐dimensional genome scanning based on the nuclear architecture of telomeres

“…Various cancers have been associated with short telomeres like esophageal squamous cell carcinoma (13). Other data demonstrate that telomere attrition is a common early alteration in many human cancers, including gastric cancer (45,46), colon cancer (47), lung cancer (48), and breast cancer (6,49). Telomere dysfunction is also associated with bone marrow failure (50), specifically MGUS and multiple myeloma (51,52).…”

Pharmacogenomic Approach of Telomerase in Cancer: Importance of End Zone Variability

“…As mentioned above, telomere shortening appears to be a signal for replication arrest in many cells. However, in some cells, rather than inducing cell cycle arrest, the substantial shortening of telomeres results in cycles of end-to-end fusions and BFB (Chin, de Solorzano et al 2004;Lantuejoul, Soria et al 2005). In most cells, damage-surveillance mechanisms detect genomic instability and induce cell death.…”