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Loss of Heterozygosity Patterns Provide Fingerprints for Genetic Heterogeneity in Multistep Cancer Progression of Tobacco Smoke–Induced Non–Small Cell Lung Cancer

Departments of ¹ Medicine (Genetics Program and Cancer Research Center), ² Genetics & Genomics, and ³ Pathology & Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts; and ⁴ Head and Neck Cancer Research Division, Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland

Requests for reprints: Sam Thiagalingam, Department of Medicine (Genetics Program and Cancer Research Center), Boston University School of Medicine, 715 Albany Street, L320, Boston, MA 02118. Phone: 617-638-6013; Fax: 617-638-4275; E-mail: samthia{at}bu.edu.

Dilution end point loss of heterozygosity (LOH) analysis, a novel approach for the analysis of LOH, was used to evaluate allelic losses with the use of 21 highly polymorphic microsatellite markers at nine chromosomal sites most frequently affected in smoking-related non–small cell lung cancers. Allelotyping was done for bronchial epithelial cells and matching blood samples from 23 former and current smokers and six nonsmokers as well as in 33 adenocarcinomas and 25 squamous cell carcinomas (SCC) and corresponding matching blood from smokers. Major conclusions from these studies are as follows: (a) LOH at chromosomal sites 8p, 9p, 11q, and 13q (P > 0.05, Fisher's exact test) are targeted at the early stages, whereas LOH at 1p, 5q, 17p, and 18q (P < 0.05, Fisher's exact test) occur at the later stages of non–small cell lung cancer progression; (b) LOH at 1p, 3p, 5q, 8p, 9p, 11q, 13q, 17p, and 18q occurs in over 45% of the tobacco smokers with SCC and adenocarcinoma; (c) compared with bronchial epithelial cells from smokers, there is a significantly higher degree of LOH at 1p, 5q, and 18q in adenocarcinoma and at 1p, 3p, and 17p in SCC (P < 0.05, Fisher's exact test). We propose that lung cancer progression induced by tobacco smoke occurs in a series of target gene inactivations/activations in defined modules of a global network. The gatekeeper module consists of multiple alternate target genes, which is inclusive of but not limited to genes localized to chromosomal loci 8p, 9p, 11q, and 13q.

Key Words: LOH • BEC • SCC • ADC • NSCLC • tobacco smoke • gatekeeper • network • allelic loss • tumor progression • lung cancer

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