Abstract 4529: The tumor molecular landscape of nasopharyngeal carcinoma (NPC) in endemic and non endemic areas

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy with a higher incidence in Asian endemic areas (EA) than in non endemic areas (NEA). Epstein-Barr virus infection is associated with most NPCs in both areas. We dissected the gene expression (GE) and microenvironment of NPC, leading to the identification of molecular subtypes that might explain the differences between EA and NEA NPCs. We retrieved data from NPC-EA transcriptomic repositories: 6 GE datasets, including tumor and normal samples (GSE12452, GSE34573, GSE132112, GSE53819, GSE68799, GSE102349); one validation dataset with both EA and NEA(https://doi.org/10.5281/zenodo.5347891); 4 GE signatures associated with prognosis and treatment prediction (PMID: 24297049, 35262435, 32596151, 33096113); and NPC EBV related genes/pathways and gene sets (PMID: 35846746, 35394843, 35105963; Liu NPC, Wood EBV EBNA1 Down, Sengupta NPC LMP1 UP, REACTOME DNA Repair; Hallmarks). The 6 datasets were integrated using a bioinformatic meta-analysis approach, and the classifier method was applied to the validation dataset in order to identify the subtype with worst prognosis. Furthermore, RNA sequencing was performed on 50 Italian NEA NPC samples (INT188/19; GSE208281). Biological and functional profiling of EA and NEA were performed using xCell, Gene set enrichment analyses, and treatment prediction methods (PMID: 16103067, pRRophetic R, PMID: 28052254). Four clusters (Cl) were identified through a meta-analysis of EA-NPC. Prognostic analyses revealed that Cl3 had the worst prognosis (P=0.0476), confirmed by three of the four prognostic signatures and in the validation dataset (P=0.0368). Based on the biological and functional characterization of these clusters, we arrived at the following GE subtypes: Cl1, Immune-active; Cl2, Defense-response; Cl3, Proliferation; Cl4, Perineural-interaction/EBV-exhaustion. According to the treatment prediction methods, the sensitivity of each cluster was radiotherapy and immunotherapy for immune-active, radiochemotherapy and immunotherapy for defense-response, chemotherapy for proliferation, and cisplatin treatment for perineural-interaction/EBV-exhaustion. In our NEA cohort, only three clusters were expressed (excluding perineural-interaction/EBV-exhaustion). Immune/biological characterization and treatment prediction analyses of NEA partially replicated the EA results. Our study provides a relevant biological overview of EBV-related NPC in both EA and NEA. The immune microenvironment plays a critical role in NPC owing to the viral etiology of this malignancy. The presence of a perineural-interaction/EBV-exhaustion cluster in EA suggests an inactive EBV infection according to the viral related “hit and run theory”; however, further analyses are needed. The immune/biological characterization of EA and NEA may help predict the response to different therapeutic strategies. Citation Format: Deborah Lenoci, Carlo Resteghini, Mara Serena Serafini, Federico Pistore, Silvana Canevari, Brigette B.Y. Ma, Stefano Cavalieri, Annalisa Trama, Lisa Licitra, Loris De Cecco. The tumor molecular landscape of nasopharyngeal carcinoma (NPC) in endemic and non endemic areas. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4529.