115. Standardized assessment of Oncogenicity and clinical significance of NTRK fusions

Abstract

Gene fusions involving the neurotrophic receptor tyrosine kinase genes (NTRK1, NTRK2, and NTRK3) are well established oncogenic drivers in a broad range of pediatric and adult tumors, and important diagnostic and therapeutic markers predicting response to FDA approved kinase inhibitors. Accurate interpretation of the clinical significance of NTRK-fusions is a high priority for diagnostic laboratories, but remains challenging and time consuming given the rapid pace of new data accumulation, the diversity of fusion partners and tumor types, and heterogeneous and incomplete information in variant knowledgebases. The ClinGen NTRK-Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) was formed to systematically address these challenges and create a resource of high-quality clinically significant assertions in the CIViC knowledgebase to support clinicians, researchers, patients and their families in making accurate interpretations and informed treatment decisions for NTRK-fusion driven tumors. As the first ClinGen VCEP formed to focus on somatic alterations, our group of researchers and clinicians has pioneered an evidence-based classification system for assessing oncogenicity and functional validity of NTRK-fusions (Oncogenic, Likely oncogenic, Unknown significance, and Benign) through the compilation of key fusion element annotations (e.g., fusion transcript structure, cancer association, and clinical validity). Additionally, the NTRK-Fusions SC-VCEP has developed specifications of AMP/ASCO/CAP rules to determine the diagnostic, prognostic and predictive significance of NTRK-fusions. Finally, detailed aggregation and analysis of NTRK-fusions represented in public fusion databases has allowed us to determine gaps and prioritize curation activities to efficiently and comprehensively curate NTRK-fusion clinical evidence, apply interpretation rules, and create high-quality publicly available clinical interpretations.