Investigation of germline PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 alterations in familial glioma

Epidemiological studies suggest that some familial aggregations of glioma m ay be due to inherited predisposition. Many genes involved in familial canc ers are frequently altered in the corresponding sporadic forms. We have inv estigated several genes known to be altered in sporadic gliomas for their p otential contribution to familial glioma, Fifteen glioma patients with a fa mily history of brain tumors were identified through the Mayo Clinic Depart ment of Neurology (nine diffuse astrocytomas, two oligodendrogliomas, two m ixed oligoastrocytomas, one pilocytic astrocytoma, and one pineal glioma), Eleven of the propositi had one or more first degree relative with a glioma , Lymphocyte DNA was derived from each of the patients and analyzed by poly merase chain reaction (PCR) and direct sequencing of the PTEN, p53, p16(INK 4A)/p14(ARF), and CDK4 genes. In addition, fluorescence in situ hybridizati on (FISH) was performed on EBV-transformed lymphocytes from each affected i ndividual to detect germline copy number of the p16(INK4A)/p14(ARF) tumor s uppressor region. A p53 germline point mutation was identified in one famil y with some findings of Li-Fraumeni syndrome, and a hemizygous germline del etion of the p16(INK4A)/p14(ARF) tumor suppressor region was demonstrated b y FISH in a family with history of both astrocytoma and melanoma, Thus, whe reas germ-line mutations of PTEN, p53, p16(INK4A)/p14(ARF), and CDK4 are no t common events in familial glioma, outside of familial cancer syndromes, p oint mutations of p53 and hemizygous deletions and other rearrangements of the p16(INK4A)/p14(ARF) tumor suppressor region may account for a subset of familial glioma cases. Collectively, these data lend genetic support to th e heritable nature of some cases of glioma, Am. J, Med, Genet. 92:136-141, 2000, (C) 2000 Wiley-Liss, Inc.