Lung cancer is a leading cause of cancer death worldwide; however, despite major advances in cancer treatment during the past two decades, the prognostic outcome of lung cancer patients has improved only minimally. This is largely due to the inadequacy of the traditional screening approach, which detects only well-established overt cancers and fails to identify precursor lesions in premalignant conditions of the bronchial tree. In recent years this 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 of oncogenes. After considering the morphological modifications that occur in premalignant lesions of the bronchial tree, we analyse the alterations occurring in a series of relevant genes: p53 and its functional regulation by MDM2 and p14ARF, p16INK4, p15INK4b, FHIT, as well as LOH at important sites such as 3p, 8p, 9p and 5q. Activation of oncogenes is considered for K-ras, the cyclin D1, the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNPA2/B1), and finally the c-myc oncogene. The expression of c-myc is influenced strongly by the presence of growth factors (GFs), among which EGF is of prime importance, as well as its receptor coded for by the c-erbB-2 oncogene. Basic knowledge at the molecular level has extremely important clinical implications with regard to early diagnosis, risk assessment and prevention, and therapeutic targets. The novel techniques for early diagnosis and screening of premalignant lung lesions, such as fluorescence bronchoscopy, endobronchial ultrasound, spiral computed tomography combined with precise spatial localization techniques, should basically change the approach to the problems 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 accurate 'intermediate end points' will enable the effects of preventive trials to be monitored. Finally, the same molecular abnormalities may serve as 'starting points' for innovative treatments designed to restore the altered functions to normality. Recent developments in our knowledge and understanding of the molecular genetic abnormalities in premalignant lung lesions open an era of hope.
In the industrial region of La Louvière (Belgium), healthy persons, presenting at a consultation of preventive medicine, showed differences as a function of smoking and of residence in one of four areas differing in sources of emissions, population density and green zones. Smokers had significantly (P=0.05) more leukocytes microl(-1), neutrophils microl(-1), CD3+ lymphocytes (lys) microl(-1), CD4+ lys microl(-1), CD25+ lys microl(-1), higher CD4/CD8 ratio's and higher carcino-embryonic antigen serum levels but significantly lower IgG immunoglobulin and serum carotene levels than non-smokers. Compared to persons living in the 'Peripheral area', and after correction for sex, smoking status and age, persons living in the more polluted areas showed significantly more CD3+CD56+ lys microl(-1). Although about the same mean value for the CD4/CD8 ratio was found for the more polluted areas, a higher percentage of their residents showed a ratio that was either <1 or >/=2.25, significantly so for the Power Station-Landfill area. A non-significant but consistent trend towards higher lymphocyte and CD8 lys counts and higher complement C3c serum levels further suggested an association between residence in a more polluted area and immunologic features. The number of CD3+CD56+ lys microl(-1), reported to be increased in cancer patients, showed a negative correlation with the CD4/CD8 ratio (r(2)=0.132, P<0.0001).
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