Abstract PR06: The ampullary adenocarcinoma, its molecular characterization and differentiation from the pancreatic ductal adenocarcinoma, duodenal adenocarcinoma, and cholangiocarcinoma

Abstract

Abstract The ampulla of Vater is a region where the pancreatic duct, biliary duct, and intestinal duodenum converge creating a complex epithelial cellular environment from which the ampullary adenocarcinomas (AMPAC) arise to form a group of histopathologically heterogenous tumors. The confluence of three organs at the ampulla of Vater gives rise to complexity in diagnosis, treatment and outcomes. Previous studies have focused mainly on marker identification to differentiate between the AMPAC intestinal and pancreatobiliary subtypes. It is established by immunohistochemistry and expression analysis that the intestinal subtype correlates with better prognosis. However, no large scale genomic profiling has been untaken. To better understand the diverse make-up of the AMPAC subtypes and to potentially help guide treatment, we analyzed 94 AMPAC of intestinal, pancreatobiliary, and mixed subtypes; 33 cholangioadenocarcinomas (CAC); and 11 duodenal adenocarcinomas (DUOAC) and their normal matched samples by whole exome sequencing, SNP array and RNA seq. Whole exome revealed that AMPAC, DUOAC, and CAC shared in common with pancreatic ductal adenocarcinoma (PDAC) high mutation rate in KRAS and TP53, loss and mutation in CDKN2A and SMAD4. ATM, a key component of the DNA damage repair pathway significantly mutated in PDAC, was also mutated in AMPAC, but not in DUOA or CAC. In contrast, loss of function mutation in NF1, an important component of the KRAS pathway, rarely mutated in PDAC, was significantly mutated (12%) and exhibited allelic loss uniquely in AMPAC. Mutations in major gene components of the PIK and wnt signaling, observed in intestinal cancers were detected in DUOAC and AMPAC but not in CAC. The AMPAC, mutations in these genes were found in both intestinal and pancreatobiliary subtypes. We also observed microsatellite instability (MSI), a common feature of gastrointestinal cancers, in 5% AMPAC, 36% of DUOAC , and 3% CAC tumors. The MSI tumors showed mutation frequencies of 17 to 113 mutations per megabase compared to 0.1 to 9.3 mutations per megabase in non-MSI tumors. In our previous study of 94 PDAC, none were MSI. Copy number analysis by SNP array revealed frequent arm-level loss in chromosome 9p, 17p, and 18q in common with all cancers. The patters of copy number change differed most clearly between CAC and DUOAC; AMPAC shared characteristics of both. Gene expression by RNAseq revealed a strong intestinal signature, including high expression of the colon cancer biomarker KRT20, in the intestinal AMPAC but not in pancreatobiliary subtype. The theme that emerges from our study is that the AMPAC shares more similarity in molecular characteristics with gastrointestinal than pancreatic ductal cancers. Interestingly, the histological subtypes of intestinal (30), pancreatobilliary (43) or mixed (10) tumors recognized by pathologists is not strongly reflected in the molecular properties of the AMPAC tumors. Pancreatobiliary subtype shows mutations associated with intestinal tumors but not PDAC, for example 32% of pancreatobilary tumors harbor PIK3CA, PIK3R1, PTEN or wnt pathway members such as CTNNB1, and APC. Patient outcomes for these various mutation profiles are under investigation. From a clinical and therapeutic perspective, targets potentially include ERB-family, ALK and BRCA1/2, mutated tumors, which collectively represent 20% of the patients. An additional 5% of patients are MSI. MSI is a favorable prognostic marker in colorectal and endometrial cancers, and has therapeutic implications. In conclusion, future diagnosis and treatment decision may gain insight by including screening for specific mutations in the characterization of AMPAC. This abstract is also presented as Poster A1. Citation Format: Marie-Claude Gingras, Amber Johns, Anthony Gill, Michael Overman, Christian Pilarsky, Sean Grimmond, Andrew Biankin, David Wheeler, Richard Gibbs. The ampullary adenocarcinoma, its molecular characterization and differentiation from the pancreatic ductal adenocarcinoma, duodenal adenocarcinoma, and cholangiocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr PR06.