Next-Generation Sequencing In Pancreatic Cancer: Revealing Genomic Mutations Beyond Kras

208 Background: Pancreatic adenocarcinoma (PA) continues to have one of the worst prognoses of all malignancies, prompting the search for known oncogenic mutations that might be targets for therapy. Methods: We conducted a retrospective analysis of patients with PA who had next generation sequencing (NGS) performed by the Genomics and Pathology Services laboratory at Washington University School of Medicine. Some of main genes included APC, ATM, BRAF, FLT3, NOTCH1, MET, FGFR4, MAPK1, MAP2K2, IDH1, IDH2, RET, JAK2, KRAS, NRAS, PTEN, EGFR, PIK3CA, PDGFRA, RUNX1, KIT, ALK, and TP53. Fluorescence in-site hybridization (FISH) for EGFR gene amplification, and MLL and ALK gene rearrangement was also performed. Results: Among 46 patients with adequate tissue for sequencing, 36 (78.3%) had KRAS mutations (G12D: 44.4%, G12V: 33.3%, G12R:11.1%, Q61H:5.6%, G12A:2.8% and G12R:2.8%). Out of 10 patients with wild type KRAS, 7 patients had either novel mutations or potential targetable mutations (table). TP53 mutations were seen in 73.9% of patients. Among 33 novel mutations not previously described in the COSMIC database, more than 10% are predicted to have deleterious effect by PROVEAN and SIFT. For example, a G1137R variant identified in ALK is predicted to be deleterious and damaging. Of 29 patients whose tumors underwent FISH, 3 patients had EGFR gene amplification, 1 patient had both EGFR gene amplification and ALK gene rearrangement, and 1 patient was positive for the MLL gene rearrangement. Conclusions: NGS of pancreatic cancer not only confirmed common mutations such as KRAS and TP53, but also revealed genomic alterations that may potentially be responsive to available targeted agents. The discovery of novel mutations in wild type KRAS tumors warrants further investigation. [Table: see text]