Next-generation sequencing (NGS)-based profiling of pancreatic acinar cell carcinoma for identification of a recurrent SND1-BRAF fusion.

11029 Background: Pancreatic acinar cell carcinoma (ACC) is a rare subtype of pancreatic cancer with a poor prognosis. Chemotherapy and radiation therapy have limited efficacy against these tumors, and novel treatment strategies are needed. Previous whole exome sequencing studies have classified these tumors as genomically heterogeneous with distinct genomic profiles from other pancreatic cancers (Jiao et al., 2013). To identify genomic alterations that could serve as potential therapeutic targets, we profiled a small set (n=3) of pancreatic ACC tumors. Methods: Extracted tumor DNA underwent hybrid capture for 3,769 exons from 236 cancer-related genes plus 47 introns of 19 genes frequently rearranged in cancer and was sequenced to an average median depth of 728x. Sequences were assessed for base substitutions, insertions and deletions, rearrangements, and copy number changes. We characterized signaling properties of confirmed molecular alterations by ectopic expression of engineered cDNAs in 293H cells. Results: We observed an average of two genomic alterations per tumor. A recurrent SND1-BRAF rearrangement was identified in two samples that lacked other known driver events. This fusion was similar in structure to other reported BRAF fusions, and preserves the serine-threonine kinase domain of the protein. In vitro studies of SND1-BRAF suggest that it activates MAPK signaling, which can be inhibited by trametinib and sorafenib. Conclusions: Although the number of samples in this study is small, fusions involving BRAF potentially occur at a high frequency in pancreatic ACC and may represent a novel therapeutic target in this disease. These alterations occur within intronic regions, and may be missed by sequencing methods that investigate exonic regions only. Preclinical data suggest that SND1-BRAF driven activation of MAPK signaling can be inhibited with existing targeted agents, suggesting that a subset of this virulent disease may be amenable to treatment with available therapies. NGS-based profiling of an expanded cohort of pancreatic ACC tumors is ongoing to determine the overall frequency of BRAF fusions in this disease.