Telomere Maintenance and DNA Damage Responses during Lung Carcinogenesis

Abstract

Purpose: Telomere shortening is an early event in bronchial carcinogenesis, preceding P53/Rb pathway inactivation and telomerase reactivation, and leading to DNA damage responses (DDR). As their inactivation in cancer increases genetic instability, our objective was to identify the chronology of telomere machinery critical events for malignant progression.Experimental Design: We have evaluated telomere length by fluorescence in situ hybridization and analyzed DDR proteins p-CHK2, p-ATM, and p-H2AX, and telomeric maintenance proteins TRF1 and TRF2 expression by immunohistochemistry in normal bronchial/bronchiolar epithelium, and in 109 bronchial preneoplastic lesions, in comparison with 32 squamous invasive carcinoma (SCC), and in 27 atypical alveolar hyperplasia (AAH) in comparison with 6 adenocarcinoma in situ (AIS; formerly bronchiolo-alveolar carcinoma) and 24 invasive adenocarcinoma (ADC).Results: Telomere length critically shortened at bronchial metaplasia stage to increase gradually from dysplasia to invasive SCC; in bronchiolo-alveolar lesions, telomere length decreased from normal to AIS and increased from stage I to II to stage III to IV ADC. Expression of TRF1 and TRF2 increased progressively from dysplasia to SCC and from AAH to invasive ADC. The expression of concomitant DDR proteins increased significantly from low-to high-grade dysplasia and from AAH to AIS and stage I to II ADC. P-CHK2 and p-H2AX expressions were highly correlated and both decreased, along with p-ATM, in SCC and advanced ADC.Conclusion: Telomere attrition occurs at the earliest stage of lung carcinogenesis as an initiating event, preceding TRF1 and TRF2 overexpression for telomere stabilization. In contrast, dismiss of DDR, through p-H2AX and p-CHK2 downregulation, represents a late progressing event associated with SCC and ADC progression. Clin Cancer Res; 16(11); 2979-88. ©2010 AACR.Lung cancer remains the leading cause of cancer-related death worldwide; its poor survival being mainly due to unresectable advanced diseases at the time of diagnosis. Eighty percent to 90% of lung cancers are related to tobacco consumption and lung carcinogenesis is a multifocal ("field cancerization") and a multistep process, resulting from the sequential accumulation of molecular and genetic/epigenetic abnormalities, mostly caused by tobacco carcinogens. These abnormalities lead to the activation of growthpromoting oncogenes and the inactivation of tumorsuppressor genes, favoring proliferation and resistance to apoptosis. Survival improvement will require the understanding of carcinogenesis events to identify the genetic markers of tumor initiation and progression, and to develop novel targeted therapeutic or prophylactic/preventive strategies.The main histologic types of lung cancer are small cell lung carcinoma (15%), adenocarcinoma (ADC), which increases in frequency worldwide (50%), and squamous cell carcinoma (SCC; 30%). The histologic transformation of bronchial and bronchiolo-alveolar epithelium parallels the accumulation of genetic...

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