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Cyclin D1 Overexpression in Bronchial Epithelia of Patients With Lung Cancer Is Associated With Smoking and Predicts Survival

D. Ratschiller, J. Heighway, M. Gugger, A. Kappeler, F. Pirnia, R.A. Schmid, M.M. Borner, D.C. Betticher

From the Department of Clinical Research and Institute of Pathology, Institute of Thoracic Surgery, Institute of Medical Oncology, Inselspital Bern, University of Bern, Switzerland; and Roy Castle Centre, Liverpool, UK.

Address reprint requests to D.C. Betticher, MD, Institute of Medical Oncology, University Hospital of Bern, 3010 Bern, Switzerland; email: daniel.betticher{at}insel.ch.

Purpose: Cyclin D1 is overexpressed in almost 60% of resectable non–small-cell lung cancer (NSCLC). In the absence of cyclin D1 gene amplification, overexpression is characterized by allelic imbalanced transcript levels.

Methods: The aims were to study cyclin D1 expression by immunohistochemistry and allelic balance of transcripts in tumor-free bronchial epithelia from patients with resectable NSCLC by using monoclonal antibodies (48 patients and 288 sites), microdissection/reverse transcriptase polymerase chain reaction/restriction fragment length polymorphism analyses (24 patients and 144 sites). Derived data were related to patient characteristics—in particular, smoking habits.

Results: In 167 (58%) of 288 sites, cyclin D1 was overexpressed, with cytoplasmic and nuclear sublocalization in 53% and 7% of all sites, respectively. Nuclear overexpression was more frequent in premalignant versus normal or hyperplastic epithelia (55% v 3%; P < .0001). Allele-specific expression imbalances were found in 69 (48%) of 144 sites; in particular, those in which cyclin D1 was overexpressed (P = .004). In 14 (58%) of 24 patients, balanced or imbalanced transcript ratios and degree of expression were consistent at all sites for the same patient, whereas in another 10 patients, transcript balances and cyclin D1 expression patterns varied across the sites. Nuclear cyclin D1 expression in at least one site (14 of 48 patients) was linked to heavy smoking (> 40 pack-years; P = .02) and shorter overall survival (P = .01).

Conclusion: Allele-specific, probably damage-driven, deregulation of the cyclin D1 gene may precede and perhaps facilitate the spread of preneoplastic clones across the bronchial epithelial surface in a significant number of patients. Cyclin D1 expression at multiple bronchial sites may identify a subgroup of heavy-smoking patients with poor outcome.

This work was funded by the Swiss Cancer League (KFS-703-8-1998). J.H. is funded by the Roy-Castle-Foundation, UK.

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