) The cellular and molecular genetics of MM are poorly understood. However, studies supported by this program grant have revealed that chromosome 13 deletion is the major adverse feature for patient outcome. Scrutiny of our extensive cytogenetic database, with more than 1000 patients, has identified 13q14 as the most frequently involved band among those with chromosome 13 deletions (greater than 90 percent). Unlike conventional metaphase analyses which demonstrate chromosome 13 deletions in no more than 20 percent and interphase FISH with the RB1 gene in up to 50 percent, our preliminary data with 12 molecular probes spanning the entire chromosome 13 q-arm revealed deletions in 14/16 (87 percent) patients. In all cases, the deletions involved the marker D13S272, which was the sole anomaly in three cases. So far, deletion patterns were independent of extent of prior therapy. Toward the goal of identifying myeloma specific tumor suppressor genes, this project will pursue two specific aims. (1) Using triple color interphase FISH, we will define in detail the minimal deleted region(s) of chromosome 13 in cells from newly diagnosed and previously treated patients entered into clinical trials of Projects 1 and 2. Serial sampling will permit investigation of anticipated evolution in chromosome 13 deletions during disease progression. (2) On the basis of both deletion frequency and deletion relatedness to clinical course (Project 1 and 2; SCID-hu readout, Project 5), we will positional clone the affected gene(s), elucidate their function in myeloma development, with the ultimate goal to develop gene-based therapies.
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