Abstract LB-313: Integrative genomic profiling of Asian gastric cancers identifies four subgroups with distinct pathobiology and prognosis

Abstract

Abstract Gastric cancer is the 2nd most common cause of cancer related mortality and 4th most common cancer worldwide. The molecular classification of Gastric Cancers and the relevance of pre-clinical models are not well established, creating challenges in discovering novel molecularly targeted therapies. In order to address that, we conducted integrated molecular data analysis of 300 Asian Gastric tumors through the Asian Cancer Research Group (ACRG). We identified four cancer subtypes, based on RNA/DNA profiling, Lauren's histological classification (Intestinal and Diffused) and Epstein Barr Virus (EBV) status, exhibiting differential pathobiology as well as prognosis. The groups are 1) Mesenchymal subgroup characterized by Diffused tumors with hallmarks of Epithelial to Mesenchymal transition such as CDH1 loss and co-occurring with IGF2 over-expression; 2) Microsatellite instable (MSI) subgroup characterized by predominantly hypermutated Intestinal tumors (including majority of mutations in KRAS) with likely MLH1 loss through promoter methylation; 3) TP53 pathway active subgroup with Epstein-Barr virus (EBV) infection or mutated oncogenes (e.g. PIK3CA) and 4) TP53 pathway inactive characterized by p53 loss through deleterious mutations in TP53 or MDM2 amplification and further characterized by both focal amplifications in oncogenes such as HER2, EGFR, cMET, CCNE1 as well as large scale chromosomal gains and losses. The above subtypes exhibited differential prognosis with the Mesenchymal subtype displaying the worst prognosis and the MSI subtype the best prognosis among the subtypes. The subtypes and their association with prognosis were independently validated in an additional large Gastric cancer cohort (N=277). We studied the applicability of this classification in other gastrointestinal (GI) cancers and show the presence of our proposed molecular subtypes of Gastric cancer in Colorectal cancers as well thereby suggesting commonalities in biological processes that give rise to Gastric and Colorectal tumors and providing a common ground to classify GI cancers. We also checked the presence of Gastric cancer subtypes in pre-clinical models of GI tract cancers and found that cell line panels often used for drug discovery shown an under-representation of p53 pathway active subtype, thus possibly creating challenges in translation to clinical studies. Overall, we provide a stratification that will lay a more solid groundwork for rationally targeting Gastric Cancer by helping focus on specific altered mechanisms and/or oncogenes as well as allowing for a more rational choice of pre-clinical models in drug discovery and development. Citation Format: Razvan Cristescu, Jeeyun Lee, Michael Nebozhyn, Amit Aggarwal, Jason Ting, Swee Seong Wong, Yong Yue, Christoph Reinhard, Kyoung Kim, Ingu Do, Hongyue Dai, Andrey Loboda. Integrative genomic profiling of Asian gastric cancers identifies four subgroups with distinct pathobiology and prognosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-313. doi:10.1158/1538-7445.AM2014-LB-313