CLONING AND CHARACTERIZATION OF HUMAN CHROMOSOME 3P TUMOR SUPPRESSOR GENES

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The consistent deletion of chromosome 3p sequences during the development and progression of many solid tumors including lung cancer and renal cell carcinoma has led researchers to examine the short arm of chromosome 3 for the presence of tumor suppressor genes. However, there appear to be at least three distinct chromosomal regions, 3p13-p14, 3p21, and 3p25, that are deleted in different solid tumors. Thus there seems to be at least three distinct tumor suppressor loci on chromosome 3p. The first goals of the laboratory are therefore the localization, cloning and characterization of these genes. Chromosomal band 3p14.2 contains a common fragile site which has been described as the most active fragile site in the human genome. Fragile sites may predispose chromosomes to breakage and subsequent loss of DNA sequences, thus the 3p14.2 fragile site may be responsible for chromosome 3p translocations and/or deletions observed in many solid tumors. A large family was described with a constitutional translocation t(3:8) (p14.2;q24.13) that had a high incidence of renal cell carcinoma. We wish to molecularly define DNA sequences surrounding both the 3p14.2 fragile site and the familial renal cell carcinoma translocation breakpoint (also within 3p14.2) to determine: (A) if fragile site-specific chromosome breakpoints cluster at the molecular level; (B) if the familial renal cell carcinoma breakpoint is within the region containing fragile site-specific breakpoints; and (c) the molecular mechanism of chromosome fragility. These projects and a large laboratory of skilled molecular biologists provide the ideal training environment for students to learn modern molecular methodologies and the principles of scientific experimentation.