Lipomas are very common, benign tumors that are caused by abnormal growth and proliferation of adipocytes. Lipomas are usually isolated and sporadic but several large families have been described whose affected members develop multiple, primary tumors with increasing age. This genetic form of multiple lipomas, called familial lipomatosis (FL) has an autosomal dominant mode of inheritance. Cytogenetic studies of sporadic lipomas show that -70% have chromosomal aberrations, most of which are balanced translocations between chromosome 12q13-q15 and chromosome 1, 2, 4-7, 10, 11, 13, 15, 17, 21 or X. Several candidates for the FL gene map to 12q13-15 including the High Mobility Group protein (HMGI-C), a member of the CCAAT/enhancer binding protein (CHOP), Murine Double Minute 2 (MDM2), Sarcoma Amplified Sequence (SAS) and Cyclin- Dependent Kinase 4 (CDK4) genes. Finding rearranged HMGI-C or CHOP genes in isolated lipomas, uterine leiomyomata or malignant liposarcomas suggests that chimeric genes comprised of HMGI-C or CHOP and another gene as the translocation partner may cause these tumors. To map the FL gene we will: 1) obtain DNAs and lipoma samples from other FL family members, 2) test markers on 12q13-15 to determine if they or the HMGI-C, CHOP, MDM2, SAS or CDK4 genes exhibit linkage, 3) identify chromosomal translocations in lipomas from affected family members, 4) identify growth factors or other candidate genes at 12q13-15 or the translocation breakpoints and 5) if needed, perform a total genome scan to localize the FL gene. In the future we will examine the FL gene for loss of heterozygosity, deletions, rearrangements or gene fusions to identify chimeric genes or other mutations. We will determine the functional importance of and the mechanisms by which these mutations cause familial lipomatosis.
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