Chromosomal and molecular pathway alterations in the neuroendocrine carcinoma and adenocarcinoma components of gastric mixed neuroendocrine-nonneuroendocrine neoplasm

Abstract

Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive subtype of mixed neuroendocrine-nonneuroendocrine neoplasm (MiNEN) with unclear clonal origin. In this study, we analyzed high-resolution copy number (CN) profiling data using the OncoScan CNV Assay in the neuroendocrine carcinoma (NEC) and adenocarcinoma components of eight MANECs. Some common CNVs, including the gain of CCNE1 (19q12) and the loss of FAT1 (4q35.2), were frequently detected in both components; these CNVs were verified by FISH, qPCR and immunohistochemistry staining assays in samples with sufficient material. The identification of common CNVs in both components supports the likelihood of single clonal origin of morphologically heterogeneous tumor cells and suggests several novel genetic events potentially involved in the development of gastric MANEC. We also detected and validated some CNVs and alterations specific for the NEC component, such as MAPK1 loss and MAPK signaling pathway alterations, which could contribute to the neuroendocrine differentiation of gastric MANEC. In addition, we found that the NEC component presented more CNVs and greater CN loss than the adenocarcinoma component (P = 0.007 and P = 0.004, respectively); the NEC components from different cases were not clustered in the hierarchical clustering analysis, indicating the marked genetic heterogenicity of the NEC component in gastric MANEC. In summary, this study describes the cytogenetic characteristics of each component of gastric MANEC, providing some clues for further studies on the development and progression of gastric MANEC as well as providing some potential therapeutic targets.