Molecular and cytogenetic analysis of tumors in von recklinghausen neurofibromatosis

Abstract

Von Recklinghausen neurofibromatosis (NFI) is a common autosomal dominant disorder mapped to 17q 11.2 and typically characterized by the occurrence of neural crest-derived tumors. The gene has recently been cloned using reverse genetics or “positional cloning” approaches. Its function, however, remains unknown. We have performed cytogenetic and molecular analyses on 9 malignant tumors from NFI patients to look for loss of alleles or chromosome rearrangements involving chromosome 17 to test the hypothesis that the NFI gene acts as a recessive “tumor suppressor” gene. Loss of alleles on this chromosome was detected for 3 of 9 malignant tumors. Two peripheral nerve sheath tumors showed allele loss at informative loci on both the long and short arms of chromosome 17. In contrast, a glioblastoma with focal gliosarcoma showed loss of heterozygosity on the short arm of chromosome 17 only, and not at loci on the long arm. One nerve sheath tumor was previously shown by direct sequence analysis to have a point mutation at the TP53 locus at 17p 13. These data support a role for the TP53 gene or other genes on the short arm of chromosome 17 in at least some malignancies in NFI. Six other neurofibrosarcomas showed no allele loss at informative loci on chromosome 17. Cytogenetic analysis was performed on 7 tumors, including 2 with allele loss. The two tumors with allele loss showed abnormal karyotypes while all others were normal. Southern blot and pulsed-field gel analysis using probes within or closely linked to the NFI locus detected no gross deletions or rearrangements in the tumors studied. These data, together with those of others, show that loss of alleles on chromosome 17 in malignant tumors from NF I patients occurs in some tumors, but is not a consistent finding. Possible explanations for these findings in relation to NFI gene function are discussed.