Prioritization of driver mutations in pancreatic cancer using cancer-specific high-throughput annotation of somatic mutations (CHASM)

Abstract

Over 20,000 genes were recently sequenced in a series of 24 pancreatic cancers. We applied CHASM (Cancer-specific High-throughput Annotation of Somatic Mutations) to 963 of the missense somatic missense mutations discovered in these 24 cancers. CHASM identified putative driver mutations (false discovery rate ≤0.3) in three known pancreatic cancer driver genes (P53, SMAD4, CDKN2A). An additional 15 genes with putative driver mutations include genes coding for kinases (PIK3CG, DGKA, STK33, TTK and PRKCG), for cell cycle related proteins (NEK8), and for proteins involved in cell adhesion (CMAS, PCDHB2). These and other mutations identified by CHASM point to potential "driver genes" in pancreatic cancer that should be prioritized for additional follow-up.

Figure 1

Structure of the catalytic domain of PIK3CG (PDB ID: 1E8X). ATP is shown bound within the PIK3CG active site. Residues D836 and K831 are within bonding distance of metal catalyst (green sphere) and ATP alpha/beta phosphates respectively. Residue R839 is within hydrogen bonding distance of both E702 and Q705 and appears to serve as an anchor to correctly position ATP contacts along the N-terminal lobe of the catalytic domain.