Chromosome arm 3p has been widely recognized to harbor one or more tumor suppressor genes important in the development or progression of lung cancer. The minimally deleted region is quite extensive however, including over 60% of the short arm from 3p14 to p23 in SCLC. In non-SCLC, the minimally deleted region is smaller but less well defined; it appears to center around the 3p14 locus D3S3. Recent identification of an SCLC cell line with a submicroscopic deletion, the U2020 cell line, affords an opportunity to intensively investigate one small region of 3p for the presence of lung cancer associated tumor suppressor genes. the U2020 deletion is estimated to remove 4 to 5 megabases of 3p including the 3p14 locus D3S3. We have identified 7 additional markers deleted in U2020 and physically linked most of them over a region of 3.5 megabases. We have isolated yeast artificial chromosome (YAC) clones for all these markers and assembled many into contiguous cloned segments. the 33 YACs isolated so far contain about 4 megabases of the U2020 deletion. This proposal will use these YAC resources to develop a series of highly polymorphic markers along the U2020 deletion, and other selected regions of 3p. These polymorphic markers will then be used to survey lung tumors for loss of heterozygosity or small, homozygous or overlapping deletions. Tumors available for this analysis include up to 500 matched tumor-normal samples comprising non-SCLC cases and up to 200 unmatched SCLC cell lines. the primary aim of this proposal is to significantly narrow the target region within U2020 to uncover the location of one putative lung cancer tumor suppressor gene. this project will lay the foundation for future isolation and intensive study of this critically important tumor suppressor.
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