Alterations of Rb pathway (Rb-p16(INK4)-cyclin D1) in preinvasive bronchial lesions

Lung cancer results from a stepwise accumulation of genetic and molecular a bnormalities with unknown temporal relationships to precursor bronchial les ions. In a search for biomarkers of malignant progression, we analyzed the expression of the tumor suppressor gene Rb and of the proteins regulating i ts phosphorylation and function in G(1) arrest, p(16INK4A) cyclin D1, in pr einvasive bronchial lesions accompanying cancer in 75 patients, in comparis on with similar lesions in 22 patients with no cancer history. Rb was const antly expressed in preinvasive lesions, including carcinoma in situ (CIS), In contrast, p16 expression was lost in moderate dysplasia (12%) and in CIS (30%) in patients with lung cancer. p16 loss occurred exclusively in patie nts who displayed loss of p16 expression in their related invasive carcinom a. Loss of p16 expression was not seen in nine patients with dysplasia but no cancer progression. Cyclin D1 overexpression was seen in hyperplasia and metaplasia (6%), mild dysplasia (17%), moderate dysplasia (46%), and CIS ( 38 %) in patients with cancer but was lost in 5% of the patients during the process of invasion; it was also observed in patients with no cancer progr ession (14%), Our results indicate that Rb protein function can be invalida ted before invasion through alteration of the Rb phosphorylation pathway, b y p16 inhibition, and/or by cyclin D1 overexpression and suggest a role for p16 and cyclin D1 deregulation in progression of preinvasive bronchial les ions to invasive carcinoma.