GENETIC-MARKERS FOR EARLY DETECTION OF LUNG-CANCER AND OUTCOME MEASURES FOR RESPONSE TO CHEMOPREVENTION

Lung cancer is one of the leading causes of cancer death in the world. The high mortality rate for lung cancer probably results, at least in part, from the absence of standard clinical procedures for diagnosis of the disease at early and more treatable stages compared to breast, prostate, and colon cancers. The delineation of genetic alterations th at occur in lung tumorigenesis may aid in both developing molecular ma rkers for early detection and predicting of response to chemopreventio n/chemotherapy. Cytogenetic and molecular genetic studies have shown t hat mutations in protooncogenes and tumor suppressor genes (TSGs) are critical in the multi-step development and progression of lung tumors. Inactivation of TSGs are by far the most common mutational events doc umented during the development of lung cancer. For example, loss of fu nction of the Rb and/or p53 genes has been detected in both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In additio n, allelic loss analyses have implicated the existence of other tumor suppressor gene loci on 9p as well as on 3p, 5q, 8p, 9q, 11p, 11q, and 17q. We examined the short arm of chromosomes 3 and 9 for TSG loci by analyzing 23 squamous cell carcinomas of the lung with numerous micro satellite markers. On chromosome 9p. loss of heterozygosity was detect ed in all of the 23 tumors and homozygous deletions of the p16/CDKN2 l ocus were detected in 6 of the 23 (26%) tumors. In addition, a novel r egion of homozygous deletion was detected in 6 of the tumors (26%) st D9S126. The homozygous deletion of D9S126 was confirmed by fluorescent in situ hybridization (FISH) analysis of tumor tissue touch preparati ons and isolated nuclei using Fl and cosmid probes that contain D9S126 . Only one tumor harbored a homozygous deletion at both the p16/CDKN2 locus and the D9S126 locus. The data identify a region of homozygous l oss on the short arm of chromosome 9, suggesting the presence of a nov el TSC locus approximately 2.5 cM proximal to p16/CDKN2. On chromosome 3p, a similar high percentage of the tumors exhibited loss of heteroz ygosity. Also, homozygous deletions were detected in several tumors at 3p21.3. Thus, FISH analysis with probes containing the D9S126 or p16 locus could be used as molecular markers to assay sputum samples for p remalignant cells exfoliated from the bronchial epithelium. Probes fro m other chromosome regions such as 3p21 could be used in a similar man ner. (C) 1998 Wiley-Liss, Inc.