Abstract 1209: <i>FGFR2</i> translocated sinonasal adenocarcinoma: A biphasic seromucinous adenocarcinoma with a distinctive and targetable molecular phenotype.

Abstract Sinonasal adenocarcinomas (SNACs) are the second most common carcinoma category in the sinonasal tract after squamous cell carcinomas and include intestinal type adenocarcinoma, non-intestinal type adenocarcinomas and salivary-type adenocarcinomas. Surgery with postoperative radiation therapy is standard treatment for SNAC. Molecular characterization lists provisional subtypes (BRAF V600E-mutated sinonasal ductal-like tumors, MAPK / PI3-K altered SNAC, CTNNB1-mutated sinonasal carcinoma, fusion-kinase associated SNAC e.g. ETV6::NTRK3, FGFR-rearranged biphasic SNAC).We report a biphasic/basaloid SNAC (maxillary sinus epicenter, extending into nasal cavity; pT4N0M0) with a novel FGFR2::SORB3 fusion. Targeted NGS was performed with a solid tumor comprehensive assay including DNA sequencing and RNA sequencing. RNA expression profiles of 1392 genes, related to tumor-immune interaction was generated. Representative SNAC region was subjected to 10X Genomics Visium Spatial Gene Expression analysis. NGS showed 9 clinically significant variants: BMPR1A loss; DICER1 loss, FGFR2 amplification, GATA4 loss, pMITF, pNF2, PIK3R1, PTEN loss, pPTEN; TMB low, MSI stable; a novel FGFR2::SORBS3 fusion was noted on RNAseq. FGFR2 breakapart FISH showed a complex rearrangement with loss of the 3’ signal and concurrent amplification of the 5’ signal. The HTG panel showed the top upregulated IL DEGs(IL12A, SPP1, IL12RAP), with SOX2 most downregulated.ST analysis of the annotated spots demonstrated 5 distinct clusters corresponding to histologically distinct compartments (biphasic-2 clusters; monophasic/ solid/ clear-1 cluster; stroma-1 cluster; tumor-stroma interface-1 cluster). Top shared upregulated DEG were OLFM4, LTF and KRT14 while the top downregulated DEG were BPIFA1, ALOX15, and C20orf85. GSEA across several MSigDB collections showed muscle cell differentiation pathway upregulation. Phosphorylation and intracellular signaling cascade pathways PI3K-AKT, JAK, STAT3, IL6, IFNƔ response was identified in most clusters. Stromal/ tumor-stromal interface clusters were enriched for EMT pathways, followed by inflammatory response, angiogenesis, K-Ras signaling up. FGFR2 translocated SNAC may represent a distinct basaloid biphasic tumor with a seromucinous phenotype. Morphology and muscle cell differentiation enrichment suggests homology with salivary epithelial-myoepithelial carcinoma, but the ‘hotter’ immune microenvironment sets it somewhat apart from most salivary type carcinomas. FGFR2::SORBS3 is rare even among the 150+ identified partners in other tumor types (i.e. cholangiocarcinoma) but appear to function similarly, upregulating phosphorylation pathways. Recognition of this tumor subtype could help select patients potentially amenable to FDA- approved oral FGFR2 inhibitors (pemigatinib, futibatinib). Citation Format: Diana Bell, Randal S. Weber, Miao Zhang, Michelle Afkhami, Raja R. Seethala. FGFR2 translocated sinonasal adenocarcinoma: A biphasic seromucinous adenocarcinoma with a distinctive and targetable molecular phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1209.