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

Aly Abdelkareem

Jason Saliba

Dr. Jason Saliba is a Senior Scientist in the Griffith laboratory at the Washington University School of Medicine with over 10 years of experience in cancer research. Dr. Saliba’s research is focused on the development and improvement of protocols, classification guidelines, and training methods related to the curation and interpretation of clinically significant information advancing precision medicine in cancer. He was the first full-time editor of the Clinical Interpretation of Variants in Cancer (CIViC) knowledgebase, which is an open access, open source, community-driven web resource for the curation of somatic variant evidence. Dr. Saliba founded and chairs the Pediatric Cancer Curation Advancement Subcommittee (PCCAS), which is a collaboration between CIViC, the ClinGen Pediatric Cancer Taskforce, and Disease Ontology, with the goal of enhancing pediatric cancer curation and the public dissemination of high-quality childhood focused interpretations. He serves as the Coordinator of the ClinGen Somatic Cancer Clinical Domain Working Group, its Taskforces and Somatic Cancer Variant Curation Expert Panels. 


Jason Salibaa, Alanna J. Churchb, Arpad Danosc, Larissa V. Furtadod, Theodore Laetsche, Liying Zhangf, Valentina Nardig, Wan-Hsin Linh, Deb Ritteri, Marilyn M. Lie, Obi L. Griffithc, Malachi Griffithc, Gordana Racaj, Angshumoy Royk

aWashington University School of Medicine, Richmond Heights, MO, USA; bBoston Children’s Hospital and Harvard Medical School, Boston, MA, USA; cWashington University School of Medicine, St. Louis, MO, USA; dSt. Jude Children’s Research Hospital, Memphis, TN, USA; eChildren’s Hospital of Philadelphia, Philadelphia, PA, USA; fDavid Geffen School of Medicine, UCLA, Los Angeles, CA, USA; gMassachusetts General Hospital and Harvard Medical School, Boston, MA, USA; hMayo Clinic, Jacksonville, FL, USA; iBaylor College of Medicine and Texas Children’s Hospital, Houston, TX, USA; jChildren’s Hospital of Los Angeles, Los Angeles, CA, USA; kBaylor College of Medicine, Houston, TX, USA

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.