Of the 40,000 new cases yearly of small cell lung cancer (SCLC), a severe form of cancer, only 10% of the affected individuals will respond to chemotherapy. In this proposal DNA markers will be used to study the molecular pathology of a specific and consistent chromosome aberration in SCLC. SCLC has been demonstrated cytogenetically to possess a deletion in the short arm of chromosome 3 (bands p14 to p23). Molecular probes have been used to extend the cytogenetic findings, and have shown a high frequency of allele loss on the short arm of chromosome 3. The long-range goal is to identify the gene(s) affected by the 3p deletion in SCLC and to determine if there is a relationship between the deletion in SCLC and the fragile site at chromosome 3p14 and also the chromosome 3p deletion seen in other cancers. Additional informative polymorphic DNA markers specific for the 3p deletion are required for initiating a fine structural analysis of this chromosomal region, and for identifying genes that may play key roles in the pathogenesis of SCLC. Using existing polymorphic DNA markers specific for the deleted region, junction fragment, Lambda, and cosmid libraries will be screened to identify additional polymorphic DNA probes. New probes will be characterized, chromosomally mapped, and used to screen for polymorphisms i) to analyze paired normal and tumor SCLC samples, ii) to identify the limits of the SCLC deletion, iii) to analyze the fragile site and the boundaries of the SCLC deletion by pulsed field electrophoresis, and iv) to analyze the 3p deletion in other cancers. Factors that may predispose individuals to SCLC that will be examined are the unusual frequency of a DNA polymorphism D3S3 in SCLC and the susceptibility to breakage of the fragile site on chromosome 3p. The data obtained should provide molecular insight into the chromosomal changes in SCLC and other cancers and information about their relationship to the fragile site at chromosome 3p14.
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