FGFR2 translocated sinonasal adenocarcinoma: A biphasic seromucinous adenocarcinoma with a distinctive and targetable molecular phenotype

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, p MITF , p NF2 , PIK3R1 , PTEN loss, p PTEN ; 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).