Lung cancer is the first cause of cancer death worldwide. Under carcinogens exposition (tobacco, asbestos..), this cancer is the end result of a multicentric multistep process of accumulation of genetic and epigenetic abnormalities deregulating the key genes controlling cell proliferation, apoptosis, senescence, immortalization and the response to DNA damage. The clonal selection leading to proliferation and invasion is achieved by disruption of the cell growth controls with a tumor progression kinetic depending of the number and accumulation rate of molecular alterations (biomarkers). Our objectives aim to: 1) identify the biomarkers predictive of progression of preinvasive and invasive lesions, 2) understand the mechanisms of their involvement in carcinogenesis, 3) validate them for use in early diagnosis. We concentrate our research on the mechanisms of invalidation of tumor suppressor genes p53 and Rb signalling and their partners (E2F1, p14ARF) and the role of FHIT deregulation. Cell cycle deregulation largely precedes invasion and occurs early in lung cancer preinvasive states. Molecular alterations of Rb pathway involve P16ink4 (CdK inhibitor) inactivation by loss of allele (LOH) or methylation and cyclin D1 and E by upregulation, contributing to Rb phosphorylation and loss of G1 arrest. In the same way FHIT inactivation occursvery early under carcinogen induced DNA damage through LOH and methylation leading to loss of checkpoint and apoptosis. These events are measurable in primary lesions and exfoliated cells from bronchial lavages and serum DNA. A large collection of frozen tumors and preinvasive lesions with associated fluids is available to test our working hypotheses at both sites. To validate them we have included high-risk smokers in prospective protocols including endoscopic, radiological and biological survey. To establish the innovative mechanistic molecular hypothesis we have both constituted a genomic functional group and set up a number of cellular and animals models ( stably transfected cell lines expressing genes of interest under control of an inducible promoter). The exploitation of these retrospective and prospective resources is allowed by molecular in situ and proteomics platforms allowing detection of multiple proteins and nucleotides in tissue and fluids as well. This integrated approach extending from molecular basis of tumor initiation and progression to clinical application in early diagnosis aims at decreasing lung cancer death. This projects integrated in an INSERM Research Centre complies with the objectives of the Canceropôle LARA and the National Institute of Cancer to increase European competitivity.