Molecular and clinical markers outperform current clinical and imaging criteria for the diagnosis and management of patients with pancreatic cysts.

Bispecific T cell–engaging antibodies capable of specifically killing cancer cells expressing mutant RAS neoantigens were generated.

We searched for oncogenes activated by copy number increases using whole-genome sequencing data of 535 pancreatic ductal adenocarcinomas (PDACs). We found that gains of 1q were the second most common gain, occurring in 213 (39.8%) of PDACs. Single-cell analysis via fluorescence in situ hybridization on 33 cancers confirmed these results. A portion of 1q, rather than the entire 1q arm, was gained in 75 (14.0%) PDACs, allowing us to pinpoint two ~3-megabase regions of 1q that were nearly always gained. These two regions contained NCSTN and PSEN2 , genes that code two subunits of the γ-secretase complex. Evaluation of 267 precancerous lesions revealed that extra copies of NCSTN and PSEN2 were common (49%) in noninvasive neoplasms (high-grade pancreatic intraepithelial neoplasms), which are at relatively high risk for progression to PDACs, but uncommon (6%) in low-grade pancreatic intraepithelial neoplasia lesions, which have low malignant potential. We hypothesize that γ-secretase genes are genetically activated oncogenes in the early phases of pancreatic neoplasia.

Aims: Activating point mutations of GNAS at codon 201 have recently been detected in approximately two-thirds of Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas. Intraductal papillary neoplasms of the bile ducts (IPNBs) morphologically resemble pancreatic IPMNs. Thus, we sought to assess the mutational status of GNAS at codon 201 in IPNBs. Methods: Thirty-four patients from three institutions were included and DNA from microdissected IPNBs was subjected to a sensitive PCR/ligation method for the detection of GNAS mutations at codon 201 and of KRAS mutations at codon 12. Mutational status was compared with clinical and pathologic data. Results: The IPNBs had a median diameter of 3.5cm and were located intrahepatic (N=6), extrahepatic (N=13), both intra- and extrahepatic (N=4), or in the gallbladder (intracystic papillary neoplasms, N=11). Most exhibited pancreatobiliary differentiation (N=20), had high-grade dysplasia (N=26), and an associated adenocarcinoma (N=20). Analysis of GNAS codon 201 identified only one mutant sample in a multifocal intestinal subtype intrahepatic IPNB with high-grade dysplasia. Six lesions harbored a KRAS codon 12 mutation. Discussion: GNAS codon 201 mutations are uncommon in IPNBs, in contrast to pancreatic IPMNs. This finding might be important for biomarker applications in order to distinguish IPNBs from IPMNs – for example in the ampullary region where both entities may be located. A more comprehensive molecular profiling is needed to uncover the pathways involved in IPNB development.