Molecular and cytogenetic analysis of tumors in von recklinghausen neurofibromatosis

Abstract

Von Recklinghausen neurofibromatosis (NF1) is a common autosomal dominant disorder mapped to 17q11.2 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 NF1 patients to look for loss of alleles or chromosome rearrangements involving chromosome 17 to test the hypothesis that the NF1 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 17p13. 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 NF1. 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 NF1 locus detected no gross deletions or rearrangements in the tumors studied.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurofibromin as a regulator of melanocyte development and differentiation

“…Both malignant (Glover et al, 1991;Menon et al, 1990;Skuse et al, 1989;Xu et al, 1992) and benign tumors (Colman et al, 1995;Sawada et al, 1996;Serra et al, 1997) in NF1 have been associated with somatic loss of the second, wild-type NF1 allele. However, studies of CALMs have not found evidence of lesional loss of the second allele (Eisenbarth et al, 1997).…”

Quest: A New Approach to Molecular Staging of Tumors

“…Consistent with CGH analysis, the karyotype of NFl-associated MPNST-derived cells are complex with chromosomal numbers ranging from 34-270 indicative of hypodiploidy, hypotriploidy, hypotetraploidy and hypertriploidy and hypertetraploidy (109,116,125 and references therein). While breakpoints were frequent, a common specific breakpoint was not detected.…”

“…Whether other cellular components of neurofibromas show cytogenetic abnormalities is unclear. Some neurofibroma fibroblastlike derived cultures were reported to show an increased frequency of chromosomal aberrations (108), while others were typically negative (109).…”

Quest: A New Approach to Molecular Staging of Tumors

“…The homozygous inactivation of NFl in NFl-associated MPNST, first reported by Skuse et al (60), has been confirmed in about 50% of tumors (n=22) by LOH (67,109,112,114,115). Mutations in both NFl alleles have been identified in a single MPNST (114).…”