Abnormal expression of CCNDI and RBI in resection margin epithelia of lung cancer patients

Abstract

Summary Tumours develop through the accumulation of genetic alterations associated with a progressive increase of the malignant phenotype. In lung cancer, chronic exposure of bronchial epithelium to carcinogens in cigarette smoke may lead to multiple dysplastic and hyperplastic lesions scattered throughout the tracheobronchial tree. Little is known about the genetic alterations in such lesions. This study was carried out to examine cyclin Dl (CCND1) and retinoblastoma (RB1) gene expression in the bronchial epithelium of patients with lung cancer. Lung tumours and their corresponding tumour-free resection margins from 33 patients who underwent resection of non-small-cell lung cancer (NSCLC) were examined by immunostaining with monoclonal antibodies against cyclin Dl (DCS-6; Novocastra) and pRb (NCL Rb-1; Novocastra). Examination of the resection margins revealed four carcinomas in situ, 19 hyperplasias and ten sections showing apparently normal bronchial epithelium. A control group of patients, without lung tumours and who had never smoked, revealed no or weak cyclin Dl and positive pRb staining within bronchial epithelia. Increased cyclin Dl and diminished pRb expression were found in 76% (n = 25) and 27% (n = 9) of the resection margins respectively, and in 12% (n = 4) both cyclin Dl and pRb expression were altered. In the corresponding tumours, 48% (n = 16) were normal, while altered expression was found for cyclin Dl in 33% (n = 11), pRb in 27% (n = 9) and both in 9% (n = 3) of cases. It appears that altered expression of cyclin Dl and pRb is an early event in NSCLC development in almost half of cases analysed. Further investigations are needed to determine the significance of immunostaining of bronchial specimens in individuals at risk of lung cancer, with the possibility that the observations are of importance in the early diagnosis of NSCLC.Keywords: non-small-cell lung cancer; carcinogenesis; cyclin D1; CCND1; retinoblastoma protein; RB1; carcinoma in situ Lung cancer has become a worldwide problem with a greater than tenfold increase in incidence of reported disease since 1930. Chronic exposure to bronchial irritants appears to lead to epithelial changes, scattered throughout the tracheobronchial tree (Auerbach et al, 1962a(Auerbach et al, ,b, 1975. Patients with lung cancer have a much greater frequency of epithelial hyperplasia in main bronchi (>90%) compared with patients (10%) who have never smoked (Auerbach et al, 1961). The best evidence for an association between carcinoma in situ and invasive carcinoma probably comes from sputum cytology from uranium miners, which showed increasingly abnormal epithelial cells as the patients progressed towards invasive lung tumours (Saccomanno et al, 1974). These results suggest that the whole tracheobronchial tree is affected by carcinogen exposure. Cells with genetic lesions resulting in a growth advantage are likely to replace the epithelium of the whole tracheobronchial tree and, in the case of additional genetic events, may show invasive growth (Thibervill...

EGFR/erB-1, HER2/erB-2, CK7, LP34, Ki67 and P53 expression in preneoplastic lesions of bronchial epithelium: an immunohistochemical and genetic study

“…As other authors observed, the intensity of Ki67 expression is also higher in dysplasia. This way, we reinforce the utility of Ki67 as a biomarker, namely for dysplasia, as it appears as a group characterized by high proliferative index, subscribing the literature and other authors' study of preneoplastic lesions [22][23][24][25][26]59]. P53, the "guardian" maintaining the integrity of the genome by participating in the DNA damage checkpoints in the cell cycle, regulating cellular proliferation and apoptosis [20], has been detected in preneoplastic lesions of the lung, suggesting that it occurs early during lung carcinogenesis [14,18,20] as the obtained results confirmed.…”

“…[18][19][20]. Those genomic and molecular abnormalities are early events in lung carcinogenesis and can persist in bronchial lesions for months or years and their persistence or regression have been correlated with lesions' evolution [15,[21][22][23][24][25][26][27][28][29][30]. Molecular changes are recognized not only in lung cancer, but also in bronchial epithelium and parenchyma of current and former smokers without the development of lung cancer [31,32].…”

Maspin – the most commonly-expressed gene of the 18q21.3 serpin cluster in lung cancer – is strongly expressed in preneoplastic bronchial lesions

“…The basal cells are multipotent reserve cells that retain the capacity to generate the various differentiated cell types of the airway epithelium. NSCLCs arise from a component(s) of this airway epithelium and it is generally possible to identify a range of pre-neoplastic lesions in the bronchial epithelia of patients, particularly smokers (Betticher et al, 1997;Ratschiller et al, 2003). Examination of multiple tumour-free sites from 20 patients allowed us to make two potentially significant observations related to the pathological expression of maspin.…”

Retinoid Targeting of Different D-Type Cyclins through Distinct Chemopreventive Mechanisms

“…(6,7). Overexpression of cyclin D1 is a frequent and early step in lung carcinogenesis (8)(9)(10)(11). Cyclin D1 overexpression is often associated with gene amplification (12) as well as allele-specific expression imbalance (11).…”