363 NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation

Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder. Patients with NF1 have mono-allelic loss of the tumor suppressor gene NF1 in their germline, which predisposes them to develop a wide array of benign lesions. Intriguingly, recent sequencing efforts revealed that the NF1 gene is frequently mutated in multiple malignant tumors not typically associated with NF1 patients, suggesting that NF1 heterozygosity is refractory to at least some cancer types. In two orthogonal mouse models representing tumors associated with NF1 (neurofibroma and malignant peripheral nerve sheath tumor) and non-NF1-related tumors (papilloma and squamous cell carcinoma), we serendipitously discover that an NF1heterozygosity microenvironment accelerates the formation of benign tumors but impairs further progression to malignancy. Analysis of benign and malignant tumors commonly associated with NF1 patients, as well as those with high NF1 gene mutation frequency, reveals an antagonistic role for NF1 heterozygosity in tumor initiation and malignant transformation and helps to reconciliate the role of the NF1 gene in both NF1 and non-NF1 patient contexts. Our novel framework to study the role of NF1 in tumorigenesis integrates the concept of NF1 as a tumor predisposition gene and we have uncovered mechanisms underlying the impairment of cancer progression by tumor microenvironment cells harboring tumor suppressor genes in the haploinsufficient state, such as NF1 heterozygosity, may translate into novel therapeutic strategies.