Different sized somatic NF1 locus rearrangements in neurofibromatosis 1-associated malignant peripheral nerve sheath tumors.

摘要

Neurofibromatosis type 1 (NF1) patients are at increased risk of developing both benign (neurofibromas) and malignant (malignant peripheral nerve sheath tumors, MPNST) tumors. Molecular data on tumor progression are scarce, and few studies have compared the NF1 locus copy number in these two tumor types. To further explore the role of such NF1 locus rearrangements in NF1 tumorigenesis, and the likely disruption to the associated genes, the NF1 gene region was analyzed in NF1-associated tumors. DNA from three MPNSTs and one neurofibroma, excised from three unrelated NF1 patients, were analyzed using an NF1 region customized array-based comparative genomic hybridization. The somatic NF1 inactivation mutational mechanisms associated with MPNSTs appear to be different from those in benign neurofibromas. Interestingly, the MPNST-associated deletion breakpoints did not involve the paralogous repetitive sequences that are involved in most germline NF1 deletions. The somatic smallest common region of deletion overlap, however, was restricted to approximately the same ~2.2-Mb interval that encompassed most of the genes deleted in NF1 recurrent constitutional deletions. A number of genes in addition to NF1 on 17q (centromere to 17q24.2) may be involved in MPNST development. A larger study is warranted to confirm these findings. As NF1 patients with such germline NF1 deletions do exhibit increased risk of developing MPNST, these present findings emphasize the likely role of at least some of these NF1 flanking genes in MPNST pathobiology.