Mechanisms of loss of heterozygosity in neurofibromatosis type 1-associated plexiform neurofibromas.

Plexiform neurofibromas constitute a serious burden for patients with neurofibromatosis type 1 (NF1), a common autosomal dominant disorder characterized by pigmentary changes and tumorous skin lesions (neurofibromas). Despite the prominence of these benign tumors in NF1 patients, the mechanisms underlying the tumor-associated loss of heterozygosity (LOH) in plexiform neurofibromas have not been extensively studied. We performed LOH analysis on 43 plexiform neurofibromas from 31 NF1 patients, the largest study of its kind to date. A total of 13 (30%) plexiform neurofibromas exhibited LOH involving 17q markers. In three tumors, LOH was found to be confined to the NF1 gene region. However, in none of the tumors was a somatic NF1 microdeletion, mediated by non-allelic homologous recombination between either NF1-REPs or SUZ12 genes, detected. Thus, NF1 microdeletions do not appear to be frequent somatic events in plexiform neurofibromas. Determination of NF1 gene copy number by multiplex ligation-dependent probe amplification indicated that although tumors with smaller regions of LOH were characterized by 17q deletions, no NF1 gene copy number changes were detected in six plexiform neurofibromas with more extensive LOH. To our knowledge, mitotic recombination has not previously been reported to be a frequent cause of LOH in plexiform neurofibromas.