Abstract 2730: Additional mutations in genes relevant to the Ras signaling pathway promote the malignant characteristics of NF1-associated malignant peripheral nerve sheath tumor (NF1-MPNST) cells

Malignant peripheral nerve sheath tumors (MPNST) are soft tissue sarcomas surrounding the peripheral nerve and occur sporadically or more often in association with neurofibromatosis type 1 (NF1, von Recklinghausen disease), which is an inherited disease caused by NF1 gene germline mutations. The NF1 tumor suppressor gene encodes neurofibromin and is a functional Ras GTPase-activating protein (RasGAP) that regulates the Ras signal negatively by accelerating the conversion of activated Ras-GTP to inactive Ras-GDP. We hypothesized that additional genetic alterations promote malignancy of NF1-associated tumors. Hence, we inoculated a GFP-labeled human NF1-MPNST cell line, sNF96.2-GFP, which has a frame-shift mutation (c.3683delC, p.Asn1229MetfsTer11) in the NF1 gene, into the renal sub-capsules of immunodeficient mice. A subclonal cell line, the A-1 cell, was established from the developed tumor. We found that A-1 cells show much higher tumorigenic activity and Akt activation than parental sNF96.2-GFP cells. We analyzed the genomic DNA of both the sNF96.2 and the A-1 cells by using the next-generation sequencing and the medical exome panel including 4813 genes, which are known to be responsible for most human genetic disorders. We identified 18 heterozygous variants in 17 genes that were present in the A-1 cells, but not in the original sNF96.2 cells. Two of these genes are associated with the regulation of the Ras signaling pathway. Our data suggests that the additional gene mutations that regulate Ras pathways do in fact promote the malignant characteristics of NF1-associated tumors through the Akt activation. Citation Format: Yoshimi Arima, Kenjiro Kosaki, Chikako Hirose, Hideyuki Saya. Additional mutations in genes relevant to the Ras signaling pathway promote the malignant characteristics of NF1-associated malignant peripheral nerve sheath tumor (NF1-MPNST) cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2730. doi:10.1158/1538-7445.AM2015-2730