Highlights
- •A systematic framework for evidence assessment of pathogenic fusions is needed.
- •Curation standards for NTRK fusions developed by the clingen somatic cancer NTRK fusions SC-VCEP would enable effective and consistent clinical interpretation of pathogenic fusions.
- •Curated evidence in existing databases for NTRK fusions are broadly variable.
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.
These fusions are also important actionable markers, predicting often dramatic 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
databases and knowledgebases. The ClinGen NTRK Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) was formed to systematically
address these challenges and create an expert-curated resource to support clinicians,
researchers, patients and their families in making accurate interpretations and informed
treatment decisions for NTRK fusion-driven tumors. We describe a system for NTRK fusion interpretation (including compilation of key elements and annotations) developed
by the NTRK fusions SC-VCEP. We illustrate this stepwise process on examples of LMNA::NTRK1 and KANK1::NTRK2 fusions. Finally, we provide detailed analysis of current representation of NTRK fusions in public fusion databases and the CIViC knowledgebase, performed by the
NTRK fusions SC-VCEP to determine existing gaps and prioritize future curation activities.
Keywords
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References
- Safety and antitumor activity of the multitargeted Pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1).Cancer Discov. 2017; 7: 400-409
- Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children.N Engl J Med. 2018; 378: 731-739
- NTRK fusion-positive cancers and TRK inhibitor therapy.Nat Rev Clin Oncol. 2018; 15: 731-747
- A paradigm shift in biomarker guided oncology drug development.Ann Transl Med. 2019; 7: 148
- First FDA approval agnostic of cancer site - when a biomarker defines the indication.N Engl J Med. 2017; 377: 1409-1412
- Detection of tumor NTRK gene fusions to identify patients who may benefit from tyrosine kinase (TRK) inhibitor therapy.J Mol Diagn. 2019; 21: 553-571
- Identifying patients with NTRK fusion cancer.Ann Oncol. 2019; 30 (viii16–22)
PubMed n.d. https://pubmed.ncbi.nlm.nih.gov/?term=ntrk+fusion (accessed August 12, 2021).
Mitelman F JBAMF (eds). Mitelman database of chromosome aberrations and gene fusions in cancer 2021. https://mitelmandatabase.isb-cgc.org (accessed August 12, 2021).
Archer Quiver Fusion Database n.d. http://quiver.archerdx.com/ (accessed August 12, 2021).
- COSMIC: the catalogue of somatic mutations in cancer.Nucleic Acids Res. 2019; 47: D941-D947
- A case for expert curation: an overview of cancer curation in the clinical genome resource (ClinGen).Cold Spring Harb Mol Case Stud. 2019; 5https://doi.org/10.1101/mcs.a004739
- Crowdsourcing and the feasibility of manual gene annotation: a pilot study in the nematode pristionchus pacificus.Sci Rep. 2019; 9: 18789
- ClinGen–the clinical genome resource.N Engl J Med. 2015; 372: 2235-2242
- CIViC is a community knowledgebase for expert crowdsourcing the clinical interpretation of variants in cancer.Nat Genet. 2017; 49: 170-174
- Adapting crowdsourced clinical cancer curation in CIViC to the ClinGen minimum variant level data community-driven standards.Hum Mutat. 2018; 39: 1721-1732
- Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the association for molecular pathology, American society of clinical oncology, and college of American pathologists.J Mol Diagn. 2017; 19: 4-23
- Discovery and characterization of targetable NTRK point mutations in hematologic neoplasms.Blood. 2020; 135: 2159-2170
COSMIC: The catalogue of somatic mutations in cancer - gene fusions n.d. https://cancer.sanger.ac.uk/cosmic/fusion (accessed August 12, 2021).
ChimerDB 4.0: an updated and expanded database of fusion genes n.d. https://www.kobic.re.kr/chimerdb_mirror/ (accessed August 12, 2021).
Kim P. And Zhou. FusionGDB: fusion gene annotation database n.d. https://ccsm.uth.edu/FusionGDB/index.html (accessed August 12, 2021).
- TumorFusions: an integrative resource for cancer-associated transcript fusions.Nucleic Acids Res. 2018; 46: D1144-D1149
- Standard operating procedure for curation and clinical interpretation of variants in cancer.Genome Med. 2019; 11: 76
- Ensembl 2020.Nucleic Acids Res. 2020; 48: D682-D688
- The growth arrest-specific gene product Gas6 promotes the survival of human oligodendrocytes via a phosphatidylinositol 3-kinase-dependent pathway.J Neurosci. 2003; 23: 4208-4218
- A highly conserved NTRK3 C-terminal sequence in the ETV6-NTRK3 oncoprotein binds the phosphotyrosine binding domain of insulin receptor substrate-1: an essential interaction for transformation.J Biol Chem. 2004; 279: 6225-6234
- Comparative assessment of methods for the fusion transcripts detection from RNA-Seq data.Sci Rep. 2016; 6: 21597
- Comprehensive evaluation of fusion transcript detection algorithms and a meta-caller to combine top performing methods in paired-end RNA-seq data.Nucleic Acids Res. 2016; 44: e47
- A pediatric case of pigmented epithelioid melanocytoma with chromosomal copy number alterations in 15q and 17q and a novel NTRK3-SCAPER gene fusion.J Cutan Pathol. 2020; 47: 70-75
- Sensitivity to entrectinib associated with a novel LMNA-NTRK1 gene fusion in metastatic colorectal cancer.J Natl Cancer Inst. 2016; 108https://doi.org/10.1093/jnci/djv306
- CDKN2A/B loss is associated with anaplastic transformation in a case of NTRK2 fusion-positive pilocytic astrocytoma.Neuropathol Appl Neurobiol. 2019; 45: 174-178
- NTRK fusions in osteosarcoma are rare and non-functional events.Hip Int. 2020; 6: 107-112
Article Info
Publication History
Published online: March 16, 2022
Accepted:
March 7,
2022
Received in revised form:
February 13,
2022
Received:
October 18,
2021
Identification
Copyright
© 2022 Elsevier Inc. All rights reserved.
