Molecular genetic abnormalities in premalignant lung lesions: biological and clinical implications

Lung cancer is a leading cause of cancer death worldwide; however, despite major advances in cancer treatment during the past two decades, the prognos tic outcome of lung cancer patients has improved only minimally. This is la rgely due to the inadequacy of the traditional screening approach, which de tects only well-established overt cancers and fails to identify precursor l esions in premalignant conditions of the bronchial tree. In recent years th is situation has fundamentally changed with the identification of molecular abnormalities characteristic of premalignant changes; these concern tumour suppressor genes, loss of heterozygosity at crucial sites and activation o f oncogenes. After considering the morphological modifications that occur i n premalignant lesions of the bronchial tree, we analyse the alterations oc curring in a series of relevant genes: p53 and its functional regulation by MDM2 and p14ARF, p16INK4, p15INK4b, FHIT, as well as LOH at important site s such as 3p, 8p, 9p and 5q. Activation of oncogenes is considered for K-ra s, the cyclin D1, the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA 2/B1), and finally the c-myc oncogene. The expression of c-myc is influence d strongly by the presence of growth factors (GFs), among which EGF is of p rime importance, as well as its receptor coded for by the c-erbB-2 oncogene . Basic knowledge at the molecular level has extremely important clinical i mplications with regard to early diagnosis, risk assessment and prevention, and therapeutic targets. The novel techniques for early diagnosis and scre ening of premalignant lung lesions, such as fluorescence bronchoscopy, endo bronchial ultrasound, spiral computed tomography combined with precise spat ial localization techniques, should basically change the approach to the pr oblems raised by this disease and allow for an increased discovery rate of incipient lesions. Sequential applications will lead to the identification of individuals / populations at high risk, while the availability of accura te 'intermediate end points' will enable the effects of preventive trials t o be monitored. Finally, the same molecular abnormalities may serve as 'sta rting points' for innovative treatments designed to restore the altered fun ctions to normality. Recent developments in our knowledge and understanding of the molecular genetic abnormalities in premalignant lung lesions open a n era of hope. (C) 2001 Lippincott Williams & Wilkins.