324 Abstracts /Lung Cancer 13 (1995) 323-356

Epidemiology and etiology

II-adrenergic mitogenic signal transduction in peripheral lung adenocarcinoma: Implications for individuals with preexisting chronic lung disease Park PG, Merryman J, Orloff M, &huller HM. Deparrment of Pathobiology, University of Tennessee. PO. Box 1071. Knoxville, TN 37901-1071. Cancer Res 1995;55:3504-8.

Peripheral adenocarcinoma (PAC) of the lung has increased dramatically over the last 20 years and is today the leading histological type of lung cancer in smokers and nonsmokers in industrialized countries. There is no apparent explanation for the steep rise in the number of individuals dweloping this cancer type. Using assays for the assessment of cell proliferation. receptor binding, and production of cyclic AMP (CAMP), we have identified a D-adrenergic receptor- mediated mitogenic pathway, which activates CAMP downstream. in cell lines derived from human peripheral adenocarcinomas that express features of Clara cells. Agonists of D- adrenergic receptors strongly stimulated cell proliferation, whereas antagonists of this receptor and its associated second messenger, CAMP, were potent inhibitors of this effect. Agonists of D-adrenergic receptors are the active ingredients of many decongestants and bronchodilators, and such medications are, therefore, likely to stimulate this pathway in vivo. Patients suffering from chronic upper and lower respiratory tract diseases and treated with such medications over many years may, therefore, be at a higher risk than the average population to develop PAC, particularly when simultaneously exposed to carcinogenic environmental factors such as smoking. Because the incidence of chronic respiratory tract diseases has risen in industrialized countries during the same time frame as PAC. a potential etiological link between the therapy of such nonneoplastic diseases with D- adrenergic agonists and the risk for PAC should be investigated.

Allele-specific loss in chromosome 9p loci in pnmeoplastic lesions accompanying non-small-cell lung cancers Kishimoto Y, Sugio K, Hung JY, Virmani AK, M&tire DD, Minna JD et al. Simmons Cancer Centec UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75235-8593. J Nat1 Cancer Inst 1995;87: 1224-9.

Bockgmund: Carcinogeneais is a multistep process, which may begin as a consequence of chromosomal changes. Deletions in the short arm of chromosome 9 (9~) have been observed in lung carcinomas. In addition, morphologically recognizable pmneoplastic lesions, frequently multiple in number, precede onset of invasive carcinomas. Purpose: We tested for deletions and loss of heteroaygosity (LOH) at 9p loci in preneoplastic and neoplastic foci in lungs of patients with non-small- cell lung carcinomas (NSCLCs). Methods: Seven archival, paraffin- embedded, surgically resected NSCLC specimens were selected. They were predominantly from patients with adenocarcinomas and contained multiple preneoplastic lesions, including hyperplasia, metaplasia, dysplasia, and carcinoma in situ (CIS). Fifty-three histologically identified preneoplastic and malignant lesions present in bronchi, bronchioles, and alveoli were precisely microdissected from stained tissue sections with a micromanipulator. Stromal lymphocytes were used to determine constitutional heterozygosity. The specimens were analyzed for LQH using polymemse chain reaction-baaed assays for polymorphism in dinucleotide repeats (microsatellite markers) in interferon aIfa (IFNA) and D9S171 loci on 9p. Rest&s: All seven cases were constitutionally heteroaygous for one or both microsatellite markers. Five of seven cases had LOH at one or both 9p loci in the invasive primary cancers (doubly informative cases). Four of these tive cases also revealed LOH in preneoplastic foci. In the doubly informative cases, LOH was detected

in five (38%) of 13 loci of hyperplasia, four (80%) of five loci of dysplasia, and three (100%) of three CIS lesions. LOH was detected in preneoplastic lesions from all regions of the respiratory tract, including bronchi, bronchioles, and alveoli, and involved five different cell types. The identical allele was lost from both the preneoplastic lesions and the corresponding tumors (12 of 12 lesions, 17 of 17 comparisons), a phenomenon we have referred to as ‘allele-specific mutation.’ Statistical analyses employing a cumulative binomial test demonstrated that the probabilities of such findings occurring by chance are 2.4 x lo’and 7.6 x 1w6, respectively. From comparisons with the previously published data on other chromosomal abnormalities in the same tissue specimens, it appears that LOH at 3p and 9p loci occurred early in the hyperplasia stage, but the ras gene point mutations were relatively late, at the CIS stage. Conclusions: LOH at 9p loci occurs at the earliest stage in the pathogenesis of lung cancer and involves all regions of the respiratory tract, LOH in NSCLC is not random but targets a specific allele in individuals. Studying preneoplastic lesions may help identify intermediate markers for risk assessment and chemoprevention.

Pulmonary expression of glutathione S-transferase M3 in lung cancer patients: Association with GSTMl polymorphism, smoking, and asbestos exposure Anttila S. Luostarinen L, Hitvonen A, Elovaara E, Karjalainen A. Nurminen T et al. Finnish Inst. of Occupational Health, Topeliuksenkatu 41 aA, FIN-00250 Helsinki. Cancer Res 1995;55:3305-9.

To characterize the relative roles of glutathione S-transferases (GST) M 1 and M3 in the susceptibility to lung cancer, the pulmonary expression of GSTM3 was quantified immunochemically and related to the GSTM 1 genotype in 100 lung cancer patients. Among active smokers and recent ex-smokers (for 6 years or less), parenchymal GSTM3 expression was lower in patients with a homoaygous GSTMl null genotype than in those who were GSTMl positive and had similar smoking habits (I < 0.001 and P = 0.004, respectively). However, in long-term ex-smokers (for 15 years or longer) GSTM3 was not affected by the GSTMl genotype. Among active smokers and recent ex-smokers who were homozygous GSTMl null, those with a definite or probable exposure to asbestos expressed GSTM3 at significantly higher levels than those for whom it was unlikely (P = 0.04). A similar effect of the homozygous GSTMl null genotype on GSTM3 expression was not detected in the bronchial epithelium when GSTM3 was visualized immunohistochemically. Different mechanisms may result in an increased risk of either squamous cell or adenocarcinomas in patients with the homozygous GSTMl null genotype Low expression ofCSTM3 due to smoking in the parenchymal lung of GSTMl null individuals can theoretically favor the development of adenocarcinoma. Our data indicated a predominance of this tumor type in patients with low expression of GSTM3.

Increased occurrence of cancer of the respiratory tract following exposure to tar - A retrospective view Hanke C, Scheidt R, Otto J. Arnstodter Strosse 52, D-99096 Erfrf. Zentralbl Arbeitsmed Arbeitssch Ergonomie 1995;45:274-8.

The occurrence of occupational diseases amongst the 850 employees of the former tar processing factory at Rositz/Thuringia, with 8 continned occupational cancers of the respiratory tract (6 bronchial carcinomas, 2 laryngeal carcinomas) within tbe period 1980-1990, indicates a significantly increased risk of cancer. It is recommended that cases to be expected in the future be recognised as occupational diseases in accordance with paragraph 551 Para. 2 of the RVO and taken into account in legislation relating to occupational diseases.