Abstract 1021: Detection of rare genomic fusions revealed through comprehensive genomic profiling of atypical tumors

Abstract Next-generation sequencing (NGS) of tumor tissue is the gold standard for genomic profiling of most solid cancer types, facilitating the identification of treatment options and patient management strategies by uncovering clinically actionable variants that can be targeted with biomarker-specific FDA-approved drugs. Validation of NGS assays requires large numbers of patient samples to evaluate the performance of each variant class, including single nucleotide variants, insertions and deletions, structural variants like copy number amplifications and translocations, as well as genomic signatures (microsatellite instability and tumor mutation burden). Sourcing clinical samples, however, is often a challenge due to limited number of patient samples available and more so by the biological prevalence of rare biomarkers, such as NTRK3 and RET fusions. An often-overlooked source of patient samples is those where genomic profiling is not regularly employed due to the early stage of the cancer that can be treated with curative surgical resection rather than requiring targeted precision oncology drugs. Furthermore, uncommon tumor types rarely receive comprehensive genomic profiling as it is not considered standard of care or medically necessary and therefore are not well-characterized for genomic alterations. Using the PGDx elio™ tissue complete, a 505-gene FDA-cleared NGS solid tumor profiling assay, several tumor types not traditionally profiled were assessed under investigator-initiated studies and were unexpectedly found to have an enrichment of NTRK3 and RET fusions. NTRK3 fusions, occurring in less than 1% of most adult cancers, were observed at a higher-than-expected frequency in atypical Spitz tumor, an uncommon melanocytic skin lesion normally treated through surgical resection. Other tumor types positive for this fusion were ganglioglioma and secretory carcinoma. RET fusions, with prevalence highest in papillary thyroid carcinoma at 2-5%, were also identified in atypical Spitz tumor, glioblastoma, and lung adenocarcinoma. To confirm these findings, samples were also run on a validated, modified Archer FusionPlex® solid tumor RNA-based panel targeting 142 genes. Of the 13 NTRK3 and 10 RET fusions detected by the PGDx elio tissue complete, all fusions were confirmed by the RNA-based fusion panel. These findings demonstrate the performance of PGDx elio tissue complete for rare fusion detection and also identify a unique source for these variants that are critical to biomarker validation. Additional work is warranted to establish the prevalence of these rare, targetable fusions in these tumor types which may represent a potential opportunity for targeted therapy. Citation Format: Jennifer B. Jackson, Stanislav Fridland, Behtash G. Nezami, Gunja Pathak, Jennifer Dickey, Lawrence Jennings. Detection of rare genomic fusions revealed through comprehensive genomic profiling of atypical tumors 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 1021.