Abstract A48: Multi-omics characterization of PDAC subtypes using PDX reveals that epigenetic but not genetic analysis permit a clinically relevant classification

Abstract

Abstract Genome-wide molecular profiles have been proven to be beneficial for the identification of clinically relevant tumor subtypes in many neoplastic diseases. While pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death, very few genomic and transcriptomic studies have been conducted. This is mainly due to the difficulty to obtain a suitable cohort of PDAC tumor samples. The major obstacle is the usually high proportion of non-transformed stromal cells, which can greatly hinder the analysis of carcinogenic-specific processes. Moreover, tumor cohorts requiring resection samples can be biased by the exclusion of inoperable patients, representing 85% of all patients presenting PDAC. In this study, we generated Patient Derived Xenografts (PDX) with samples collected from 29 patients using either Endoscopic Ultrasound-Guided Fine-Needle Aspirates or, for operable patients, resections. The transcriptomic profiles, of both mRNA and miRNA, and the epigenetic landscape of early PDX passages consistently identified two tumor-specific molecular subtypes: a well differentiated group often referred to as classical, and an undifferentiated group previously recognized as Basal, Quasi-Mesenchymal or Squamous. Of all the genetic alterations determined by Copy Number analysis and exome sequencing, none were specific to any of the two subtypes, which therefore could not be discriminated solely on genetic basis. These two PDAC subtypes are characterized by distinct epigenetic and transcriptomic profiles of which the analysis revealed the deregulation of several pathways previously imputed in PDAC development and carcinogenesis in general. In particular, we showed that the Wnt pathway as well as several metabolic pathways, including cytochrome P450 genes recently implicated in drug resistance, are both epigenetically and transcriptionally deregulated. Altogether, our results provide new insights on pancreatic carcinogenesis and suggest that PDAC phenotypical heterogeneity is mainly driven by epigenetic rather than genetic events. Citation Format: Remy Nicolle, Yuna Blum, Laetitia Marisa, Jonathan Garnier, Benjamin Bian, Celine Loncle, Martin Bigonnet, Odile Gayet, Vincent Moutardier, Pauline Duconseil, Mohamed Gasmi, Mehdi Ouaissi, Olivier Turrini, Marc Giovannini, Aurélie Maignan, Jean-Marie Boher, Jacques Ewald, Erwan Bories, Marc Barthet, Anthony Goncalves, Flora Poizat, Jean-Luc Raoul, Veronique Secq, Stephane Garcia, Philippe Grandval, Marine Barraud-Blanc, Emmanuelle Norguet, Marine Gilabert, Jean-Robert Delpero, Ezequiel Calvo, Aurélien de Reyniès, Nelson Dusetti, Juan Iovanna.{Authors}. Multi-omics characterization of PDAC subtypes using PDX reveals that epigenetic but not genetic analysis permit a clinically relevant classification. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A48.