A novel RAS internal tandem duplication involving the switch II domain disrupts GAP-binding and activates oncogenic signaling.

Abstract

e15069 Background: Recent clinical guidelines for expansion of molecular testing of oncogenic RAS mutations in colorectal carcinoma have led to increased identification of mutations in this patient population. The clinical characteristics of NRAS-mutated colorectal carcinoma have not been well established because of the lower prevalence of these mutations (< 6%) as compared to oncogenic KRAS mutations. Here, we report the discovery of a novel internal tandem duplication (ITD) mutation of NRAS, which disrupts the Switch II domain in an index case of a patient with widely disseminated colorectal cancer. Methods: Hotspot next generation sequencing of a brain metastasis using a clinical solid tumor panel identified this novel NRAS ITD and a TP53 missense mutation (p.P275F). Whole exome sequencing of the primary tumor and two metastatic lesions (lung and brain) was performed to identify other genetic factors potentially driving the disease. Results: The above approach confirmed that the NRAS ITD and TP53 mutation were conserved between the primary tumor and both metastatic tumors and identified an additional pathogenic mutation in CSMD1 (a tumor suppressor gene). No other clearly pathogenic driver mutations were identified. Structural biology and biochemical analyses demonstrated that the inserted 15 amino acids prevented binding to GAP protein, leading to sustained RAS activation and increased interaction with RAF to stimulate downstream MAPK activation. Conclusions: These genomic and biochemical studies indicate that a novel NRAS ITD was the primary driver mutation of this aggressive colorectal carcinoma. Identical or similar ITDs in NRAS and KRAS may also drive other forms of colorectal cancer and other aggressive malignancies and represent a new subset of RAS-driven drug-resistant cancers.