Telomere Shortening, Telomere Protein TRF1 and TRF2 Activation, and DNA Damage Response Impairement during Bronchial Carcinogenesis
S Lantuejoul, C Raynaud, S Gazzeri, D Moro-Sibilot, D Salameire, JC Soria, E Brambilla. CHU A Michallon, Grenoble, France; CEA, Fontenay aux Roses, France; INSERM U823, IAB, University J. Fourier, Grenoble, France
Background: Telomere shortening is an early event in bronchial carcinogenesis, preceding P53/Rb pathway inactivation and telomerase reactivation. It is also perceived as double strand break, leading to DNA damage responses (DDR), frequently inactivated in carcinogenesis to overcome G1 arrest or apoptosis. Concomitantly, telomere proteins TRF1 and TRF2 are potentially overexpressed due to their involvement in telomere stabilization and DDR inactivation.
Design: To establish the chronology of these abnormalities in bronchial carcinogenesis, we have assessed telomere length by FISH and evaluated by immunohistochemistry TRF1 and TRF2 expression, besides DDR proteins phosphorylated (p)-CHK2, p-ATM and p-H2AX expression in 109 preneoplastic lesions, including 15 mild dysplasia, 19 moderate dysplasia, 31 severe dysplasia, and 44 in situ carcinoma, and in 35 normal or metaplastic epithelium, and 32 squamous invasive carcinoma.
Results: Telomeres critically shorten in bronchial metaplasia to increase from mild to moderate and severe dysplasia to invasive carcinoma (p= 0.03), along with TRF1 and TRF2 overexpression (p< 0.0001 and p=0.0007 respectively). In response, p-H2AX, p-CHK2 and p-ATM expressions are already observed at metaplasia stage, with an increased overexpression in preneoplastic lesions, but a reduced expression in invasive carcinoma (p< 0.0001 for p-CHK2 and p-ATM, and p=0.0002 for p-H2AX).
Conclusions: Telomere attrition is associated with DDR activation at the earliest stage of bronchial carcinogenesis, and precedes TRF1 and TRF2 overexpression. In contrast, DDR inactivation represents the latest event, occurring in invasive carcinoma.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 249, Tuesday Afternoon