Proteogenomic interrogation of gastrointestinal neuroendocrine carcinoma.

Abstract

639 Background: Gastrointestinal neuroendocrine carcinoma (GI-NEC) is a rare and aggressive cancer with limited therapeutic availability. Proteogenomic analyses have recently garnered attention for understanding disease biology and development of therapeutic options in multiple types of cancer. This study aims to perform proteogenomic analysis using endoscopic biopsy specimens of GI-NEC to elucidate its characteristic molecular aberrations. Methods: We collected endoscopic biopsy specimens of tumors (Ts) and non-tumor adjacent tissues (NATs) obtained from untreated GI-NEC patients. Each specimen was immediately snap-frozen in liquid nitrogen within 20 seconds of collection. Ultradeep proteomic and phosphoproteomic analyses were performed using mass-spectrometry with multiplexed TMT-based quantification. Genomic analysis was conducted using a targeted high-multiplex PCR-based NGS panel. Results: Ten GI-NEC (stomach 8, esophagus 1, anal canal 1) patients were enrolled in this study. Our analysis identified 5607 proteins and 19316 class 1 phosphosites. Gene set enrichment analysis using proteomic data showed activation of cell cycle pathway and DNA repair pathway in the T group compared with the NAT group. Post-translational modifications signature enrichment analysis using phosphoproteomic data showed activation of kinases related to cell cycle (e.g., CDK1, CDK2) and DNA repair (e.g., ATR, ATM) in the T group compared with the NAT group. Compared with the NAT group, several proteins that were considered targets of antibody-drug conjugates (e.g., CEACAM5, EGFR, FN1) were highly expressed in the T group. Genomic analysis of Ts showed recurrent alterations in TP53 (100%), CDKN2A (70%), and ERAP2 (50%). Conclusions: Our study suggests that proteogenomic analysis using endoscopic biopsy specimens is a clinically relevant tool not only for understanding disease pathogenesis but also for identifying potential therapeutic targets in GI-NEC.