Telomere Maintenance and DNA Damage Responses during Lung Carcinogenesis

摘要: Purpose: Telomere shortening is an early event in bronchial carcinogenesis, preceding P53/Rb pathway inactivation and telomerase reactivation, leading to DNA damage responses (DDR). As their cancer increases genetic instability, our objective was identify the chronology of telomere machinery critical events for malignant progression. Experimental Design: We have evaluated length by fluorescence situ hybridization analyzed DDR proteins p-CHK2, p-ATM, p-H2AX, telomeric maintenance TRF1 TRF2 expression immunohistochemistry normal bronchial/bronchiolar epithelium, 109 preneoplastic lesions, comparison with 32 squamous invasive carcinoma (SCC), 27 atypical alveolar hyperplasia (AAH) 6 adenocarcinoma (AIS; formerly bronchiolo-alveolar carcinoma) 24 (ADC). Results: critically shortened at metaplasia stage increase gradually from dysplasia SCC; decreased AIS increased I II III IV ADC. Expression progressively SCC AAH The concomitant significantly low- high-grade P-CHK2 p-H2AX expressions were highly correlated both decreased, along advanced Conclusion: attrition occurs earliest lung carcinogenesis as initiating event, overexpression stabilization. In contrast, dismiss DDR, through p-CHK2 downregulation, represents a late progressing associated ADC Clin Cancer Res; 16(11); 2979–88. ©2010 AACR.