Genomic Alterations in Pulmonary Carcinoid Tumors: A Targeted Analysis of Gene Rearrangements and Oncogenic Mutations

INTRODUCTION: Pulmonary carcinoids (PCs) are rare, well-differentiated, neuroendocrine lung tumors with limited treatment options for advanced disease, underscoring the need for targeted therapies. PCs typically exhibit a low mutational burden. Although MEN1 and chromatin-modifier mutations are known contributors, potentially actionable alterations remain poorly characterized. To better define therapeutic opportunities, we evaluated oncogenic fusions and variants across 17 cancer-associated genes in a large retrospective PC cohort. METHODS: Formalin-fixed, paraffin-embedded primary tumors from Helsinki University Hospital (n = 119, collected between 1990 and 2020) were subjected to targeted RNA-based fusion and variant analysis using the Archer FusionPlex Lung v2 assay. RESULTS: The most frequent recurrent genetic rearrangements involved ALK (n = 5), BRAF (n = 3), FGFR2 (n = 3), and NTRK3 (n = 2), each featuring diverse fusion partners. Variant analysis identified BRAF, EGFR, FGFR1, and FGFR3 as the most frequently mutated genes, although only 2.2% (n = 4) of all detected variants were classified as oncogenic. Notably, 66.7% of all oncogenic or likely oncogenic variants occurred in BRAF and EGFR. Oncogenic variants were identified in ALK, BRAF, EGFR, and ERBB2. Although all FGFR1-3 variants were of uncertain significance, their frequency (34.1% of all detected variants), together with the three FGFR2 fusions, suggested that FGFR alterations may be biologically relevant in PCs. CONCLUSION: Despite the typically muted genomic landscape of PCs, our study revealed a small yet therapeutically relevant subset of alterations. The findings further characterized the molecular profile of PCs and identified potentially actionable molecular subgroups. While these alterations were not associated with disease-specific survival or metastatic status, they support consideration of molecular profiling in selected patients with advanced disease.