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Clinical Cancer Research Vol. 5, 243-250, February 1999
© 1999 American Association for Cancer Research

Advances in Brief

Alterations of Rb Pathway (Rb-p16INK4-Cyclin D1) in Preinvasive Bronchial Lesions1

Elisabeth Brambilla2, Sylvie Gazzeri, Denis Moro, Sylvie Lantuejoul, Sylvie Veyrenc and Christian Brambilla

Lung Cancer Research Group, Institut Albert Bonniot, CHU-C.J.F. Institut National de la Santé et de la Recherche Médicale, 97-01 [E. B., S. G., D. M., S. V., C. B.]; Laboratoire de Pathologie Cellulaire, Hôpital Albert Michallon, BP217 [E. B., S. L.]; and Service de Pneumologie, Hôpital Albert Michallon, BP217 [D. M., C. B.], 38043 Grenoble Cedex 9, France

Lung cancer results from a stepwise accumulation of genetic and molecular abnormalities with unknown temporal relationships to precursor bronchial lesions. In a search for biomarkers of malignant progression, we analyzed the expression of the tumor suppressor gene Rb and of the proteins regulating its phosphorylation and function in G1 arrest, p16INK4A and cyclin D1, in preinvasive bronchial lesions accompanying cancer in 75 patients, in comparison with similar lesions in 22 patients with no cancer history. Rb was constantly 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 patients who displayed loss of p16 expression in their related invasive carcinoma. 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 progression (14%). Our results indicate that Rb protein function can be invalidated before invasion through alteration of the Rb phosphorylation pathway, by p16 inhibition, and/or by cyclin D1 overexpression and suggest a role for p16 and cyclin D1 deregulation in progression of preinvasive bronchial lesions to invasive carcinoma.




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Copyright © 1999 by the American Association for Cancer Research.