A Potential Role for NF1 mRNA Editing in the Pathogenesis of NF1 Tumors

Amedeo J. Cappione, Brian L. French, and Gary R. Skuse

Summary:

Neurofibromatosis type I (NF1) is a common disorder which predisposes to neoplasia in tissues derived from the embryonicneural crest. The NF1 gene encodes a tumor suppressor which most likely acts through the interaction of its GTPase activating protein (GAP) related domain (GRD) with the product of the ras protooncogene. We have previously identified a site in the NF1 mRNA, near the 5' end of the NF1 GRD, which undergoes base-modification editing. Editing at that site changes a C to a U, thereby introducing an in-frame stop codon. NF1 RNA editing has been detected in all cell types studied to date. In order to investigate the role played by editing in NF1 tumorigenesis we analyzed RNA from nineteen NF1 tumors. We observed varying levels of NF1 mRNA editing in different tumors with higher levels of editing in more malignant tumors (e.g. neurofibrosarcomas) compared to benign tumors (cutaneous neurofibromas). Plexiform neurofibromas have an intermediate level of NF1 mRNA editing. We also compared tumor and nontumor tissues from several NF1 individuals to determine the extent of variability present in the constitutional levels of NF1 mRNA editing and to determine whether higher levels are present in tumors. The constitutional levels of NF1 mRNA editing varied slightly but were consistent with the levels observed in non-NF1 individuals. In every case there was a greater level of NF1 mRNA editing in the tumor than in the nontumor tissue from the same patient. These results suggest that inappropriately high levels of NF1 mRNA editing may play a role in NF1 tumorigenesis and that editing may result in the functional equivalent of biallelic inactivation of the NF1 tumor suppressor.