Cyclin D1 overexpression in bronchial epithelia of patients with lung cancer is associated with smoking and predicts survival.
OBJECTIVE
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).


CONCLUSIONS
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.
Ratschiller
D
D
Institute of Medical Oncology, University Hospital of Bern, 3010 Bern, Switzerland.
Heighway
J
J
Gugger
M
M
Kappeler
A
A
Pirnia
F
F
Schmid
R A
RA
Borner
M M
MM
Betticher
D C
DC
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D012150:Polymorphism, Restriction Fragment Length; D016016:Proportional Hazards Models; D011446:Prospective Studies; D020545:Respiratory Mucosa / Q000378:metabolism*; D012907:Smoking / Q000009:adverse effects*; D018709:Statistics, Nonparametric; D015996:Survival Rate; D013557:Switzerland / Q000453:epidemiology
D019938:Cyclin D1