Bioinformatics Analysis of Essential Genes in NF1 and CDKN2A Null Cancer Cell Lines

Abstract

Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome characterized by a germline loss of function mutation in the NF1 tumor suppressor gene. The heterozygous loss of one copy of this gene drives the clinical condition, but the occasional biallelic loss of NF1 in the Schwann cell lineage causes the formation of tumors called neurofibromas in almost all patients. The further loss of function of a second tumor suppressor, CDKN2A, is associated with transformation into an atypical neurofibroma, which can then transform into an aggressive malignant peripheral nerve sheath tumor (MPNSTs). Cells that lose certain genes can become more reliant on other pathways, which can be targeted for treatments in a phenomenon called synthetic lethality. Treatments of MPNST and precursor atypical neurofibromas lacking NF1 and CDKN2A have not yet been identified. Using the Cancer Dependency Map Project and Ingenuity Pathway Analysis, canonical and upstream pathway associations were identified from genes selectively essential in cell lines containing both NF1 and CDKN2A null mutations. Genes involved in estrogen receptor signaling were enriched in the list of essential genes in NF1 and CDKN2A co-deleted cells, with IGF-1, PGR, CDK8, ADCY1, and PKCε identified as potential drug targets from the pathway. The SMARCA4 upstream regulatory pathway was also found to be significantly enriched, which has previously been implicated as a synthetic lethal target for certain cancers. These targets can be used for identifying novel therapies targeting MPNST pre-malignant precursors to prevent malignant transformation of neurofibromas and improve health outcomes for NF1 patients.