{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T16:24:47Z","timestamp":1793118287289,"version":"4.5.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T00:00:00Z","timestamp":1746144000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p><jats:italic>NTRK1<\/jats:italic>, <jats:italic>NTRK2<\/jats:italic>, and <jats:italic>NTRK3<\/jats:italic> gene fusions are rare oncogenic driver alterations found in diverse tumor types of adults and children. They are clinically important biomarkers as tumors harboring these genomic alterations have high response rates to targeted therapy. Routine testing for <jats:italic>NTRK<\/jats:italic> fusions and treatment with TRK inhibitors has been recommended in multiple tumor types; however, differences between testing technologies used for detecting <jats:italic>NTRK<\/jats:italic> fusions can result in variable likelihoods of identification.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To assess the prevalence of <jats:italic>NTRK<\/jats:italic> fusions in a real-world standard-of-care setting, we analyzed data from 19,591 FFPE samples encompassing 35 solid tumor types submitted for comprehensive genomic profiling (CGP) as part of routine clinical care. CGP testing included DNA hybrid-capture sequencing to detect small variants, copy number alterations, microsatellite instability (MSI), and tumor mutational burden (TMB). RNA hybrid-capture sequencing was concurrently performed to detect fusions and splice variants. Detected <jats:italic>NTRK<\/jats:italic> fusions were categorized as oncogenic, likely oncogenic, or variant of unknown significance (VUS) based on the fusion partner, orientation, and breakpoint position.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>73 oncogenic or likely oncogenic <jats:italic>NTRK<\/jats:italic> fusions were identified in 69 unique tumor specimens across 19 tumor types for a total cohort prevalence of 0.35%. Tumor types with the highest <jats:italic>NTRK<\/jats:italic> fusion prevalence included glioblastoma (1.91%), small intestine (1.32%), and head and neck (0.95%) tumors with other solid tumor types ranging from 0.19% (uterine) to 0.63% (breast). We identified diverse intra and inter-chromosomal partner genes for <jats:italic>NTRK<\/jats:italic> fusions across all tumor types. Most <jats:italic>NTRK<\/jats:italic> fusions were detected in only one tumor specimen, though some recurrent fusions were noted with <jats:italic>ETV6<\/jats:italic>, <jats:italic>TPM3<\/jats:italic>, <jats:italic>LMNA<\/jats:italic>, <jats:italic>EML4<\/jats:italic>, <jats:italic>TPR<\/jats:italic>, <jats:italic>PEAR1<\/jats:italic>, <jats:italic>IRF2BP2<\/jats:italic>, and <jats:italic>KANK1<\/jats:italic> fusion partners. Most <jats:italic>NTRK<\/jats:italic> fusions were mutually exclusive from other genomic driver alterations, however, almost a third of tumor specimens (29%) contained at least one co-occurring genomic driver, which may affect treatment decisions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>The high prevalence of oncogenic and likely oncogenic <jats:italic>NTRK<\/jats:italic> fusions detected in our analysis suggests that RNA hybrid-capture-based sequencing for fusion detection is a highly sensitive method for identifying clinically meaningful known and novel <jats:italic>NTRK<\/jats:italic> fusions, which may be missed with other detection methods, directly impacting therapeutic options and patient outcomes.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fgene.2025.1550706","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:44:28Z","timestamp":1746186268000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["RNA hybrid-capture next-generation sequencing has high sensitivity in identifying known and less characterized oncogenic and likely oncogenic NTRK fusions in a real-world standard-of-care setting"],"prefix":"10.3389","volume":"16","author":[{"given":"Zachary D.","family":"Wallen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marni","family":"Tierno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Schnettler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Roos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Green","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kobina","family":"Amoah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca A.","family":"Previs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Hastings","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarabjot","family":"Pabla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor J.","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Caveney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcia","family":"Eisenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratheesh","family":"Sathyan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakti H.","family":"Ramkissoon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Severson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,5,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1158\/2159-8290.CD-17-0151","article-title":"AACR Project GENIE: powering precision medicine through an international Consortium","volume":"7","author":"Andr\u00e9","year":"2017","journal-title":"Cancer Discov."},{"key":"B2","doi-asserted-by":"publisher","first-page":"viii5","DOI":"10.1093\/annonc\/mdz383","article-title":"Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer","volume":"30","author":"Amatu","year":"2019","journal-title":"Ann. Oncol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2207","DOI":"10.1056\/NEJMoa2017699","article-title":"Pembrolizumab in microsatellite-instability-high advanced colorectal cancer","volume":"383","author":"Andre","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1007\/s11523-021-00815-4","article-title":"TRK fusion cancer: patient characteristics and survival analysis in the real-world setting","volume":"16","author":"Bazhenova","year":"2021","journal-title":"Target Oncol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"329","DOI":"10.6004\/jnccn.2021.0012","article-title":"Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology","volume":"19","author":"Benson","year":"2021","journal-title":"J. Natl. Compr. Canc Netw."},{"key":"B6","doi-asserted-by":"publisher","first-page":"521","DOI":"10.3390\/diagnostics10080521","article-title":"Next generation sequencing for gene fusion analysis in lung cancer: a literature review","volume":"10","author":"Bruno","year":"2020","journal-title":"Diagn. (Basel)"},{"key":"B7","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1530\/ERC-19-0414","article-title":"Heterogeneity of genomic profile in patients with HER2-positive breast cancer","volume":"27","author":"Chen","year":"2020","journal-title":"Endocr. Relat. Cancer"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1220","DOI":"10.1093\/bioinformatics\/btv710","article-title":"Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications","volume":"32","author":"Chen","year":"2016","journal-title":"Bioinformatics"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1158\/0008-5472.CAN-18-3126","article-title":"Colorectal carcinomas containing hypermethylated MLH1 promoter and wild-type BRAF\/KRAS are enriched for targetable kinase fusions","volume":"79","author":"Cocco","year":"","journal-title":"Cancer Res."},{"key":"B10","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1038\/s41571-018-0113-0","article-title":"NTRK fusion-positive cancers and TRK inhibitor therapy","volume":"15","author":"Cocco","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1422","DOI":"10.1038\/s41591-019-0542-z","article-title":"Resistance to TRK inhibition mediated by convergent MAPK pathway activation","volume":"25","author":"Cocco","year":"","journal-title":"Nat. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"e0260089","DOI":"10.1371\/journal.pone.0260089","article-title":"A scalable high-throughput targeted next-generation sequencing assay for comprehensive genomic profiling of solid tumors","volume":"16","author":"Conroy","year":"2021","journal-title":"PLoS One"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1302","DOI":"10.1158\/1078-0432.CCR-21-3597","article-title":"Updated integrated analysis of the efficacy and safety of entrectinib in patients with NTRK fusion-positive solid tumors","volume":"28","author":"Demetri","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"B14","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/S1470-2045(19)30691-6","article-title":"Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials","volume":"21","author":"Doebele","year":"2020","journal-title":"Lancet Oncol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"viii23","DOI":"10.1093\/annonc\/mdz282","article-title":"TRK inhibitors in TRK fusion-positive cancers","volume":"30","author":"Drilon","year":"2019","journal-title":"Ann. Oncol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1158\/2159-8290.CD-16-1237","article-title":"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)","volume":"7","author":"Drilon","year":"2017","journal-title":"Cancer Discov."},{"key":"B17","doi-asserted-by":"publisher","first-page":"497","DOI":"10.6004\/jnccn.2022.0025","article-title":"Non-small cell lung cancer, version 3.2022, NCCN clinical practice guidelines in oncology","volume":"20","author":"Ettinger","year":"2022","journal-title":"J. Natl. Compr. Canc Netw."},{"key":"B18","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1038\/s41379-018-0118-3","article-title":"Molecular characterization of cancers with NTRK gene fusions","volume":"32","author":"Gatalica","year":"2019","journal-title":"Mod. Pathol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1016\/S1470-2045(19)30856-3","article-title":"Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1\/2 clinical trials","volume":"21","author":"Hong","year":"2020","journal-title":"Lancet Oncol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1007\/s11523-022-00887-w","article-title":"Timing of NTRK gene fusion testing and treatment modifications following TRK fusion status among US oncologists treating TRK fusion cancer","volume":"17","author":"Klink","year":"2022","journal-title":"Target Oncol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1007\/s11523-018-0590-1","article-title":"TRK inhibition: a new tumor-agnostic treatment strategy","volume":"13","author":"Kummar","year":"2018","journal-title":"Target Oncol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/j.jtho.2016.10.007","article-title":"Checkpoint inhibitors in metastatic EGFR-mutated non-small cell lung cancer-A meta-analysis","volume":"12","author":"Lee","year":"2017","journal-title":"J. Thorac. Oncol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1093\/annonc\/mdx048","article-title":"Genomic characterization of HER2-positive breast cancer and response to neoadjuvant trastuzumab and chemotherapy-results from the ACOSOG Z1041 (Alliance) trial","volume":"28","author":"Lesurf","year":"2017","journal-title":"Ann. Oncol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1093\/annonc\/mdz204","article-title":"ESMO recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research","volume":"30","author":"Marchio","year":"2019","journal-title":"Ann. Oncol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1093\/annonc\/mdz167","article-title":"Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry","volume":"30","author":"Mazieres","year":"2019","journal-title":"Ann. Oncol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1200\/PO.18.00183","article-title":"Analysis of NTRK alterations in pan-cancer adult and pediatric malignancies: implications for NTRK-targeted therapeutics","volume":"2018","author":"Okamura","year":"2018","journal-title":"JCO Precis. Oncol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1158\/1535-7163.MCT-14-0983","article-title":"PD-L1 expression as a predictive biomarker in cancer immunotherapy","volume":"14","author":"Patel","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"B28","doi-asserted-by":"publisher","first-page":"460","DOI":"10.1136\/jclinpath-2018-205679","article-title":"Testing algorithm for identification of patients with TRK fusion cancer","volume":"72","author":"Penault-Llorca","year":"2019","journal-title":"J. Clin. Pathol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1016\/j.humpath.2018.01.007","article-title":"Uterine rhabdomyosarcoma in adults","volume":"74","author":"Pinto","year":"2018","journal-title":"Hum. Pathol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.1158\/1078-0432.CCR-19-3165","article-title":"TRK fusions are enriched in cancers with uncommon histologies and the absence of canonical driver mutations","volume":"26","author":"Rosen","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"B31","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.cancergen.2022.03.001","article-title":"Standardized evidence-based approach for assessment of oncogenic and clinical significance of NTRK fusions","author":"Saliba","year":"2022","journal-title":"Cancer Genet."},{"key":"B32","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1038\/s41588-018-0312-8","article-title":"Tumor mutational load predicts survival after immunotherapy across multiple cancer types","volume":"51","author":"Samstein","year":"2019","journal-title":"Nat. Genet."},{"key":"B33","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1093\/annonc\/mdz077","article-title":"Severe immune-related adverse events are common with sequential PD-(L)1 blockade and osimertinib","volume":"30","author":"Schoenfeld","year":"2019","journal-title":"Ann. Oncol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1115405","DOI":"10.3389\/fonc.2023.1115405","article-title":"ERBB family fusions are recurrent and actionable oncogenic targets across cancer types","volume":"13","author":"Schubert","year":"2023","journal-title":"Front. Oncol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.3390\/diagnostics12071539","article-title":"Target enrichment approaches for next-generation sequencing applications in oncology","volume":"12","author":"Singh","year":"2022","journal-title":"Diagn. (Basel)"},{"key":"B36","doi-asserted-by":"publisher","first-page":"S787","DOI":"10.1016\/j.annonc.2023.09.2405","article-title":"1372P Repotrectinib in patients (pts) with NTRK fusion-positive (NTRK+) advanced solid tumors, including NSCLC: update from the phase I\/II TRIDENT-1 trial","volume":"34","author":"Solomon","year":"2023","journal-title":"Ann. Oncol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"viii16","DOI":"10.1093\/annonc\/mdz384","article-title":"Identifying patients with NTRK fusion cancer","volume":"30","author":"Solomon","year":"2019","journal-title":"Ann. Oncol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"D1210","DOI":"10.1093\/nar\/gkad986","article-title":"COSMIC: a curated database of somatic variants and clinical data for cancer","volume":"52","author":"Sondka","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"2541","DOI":"10.1002\/cam4.4561","article-title":"NTRK fusion positive colorectal cancer is a unique subset of CRC with high TMB and microsatellite instability","volume":"11","author":"Wang","year":"","journal-title":"Cancer Med."},{"key":"B40","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/s41698-022-00325-0","article-title":"Landscape of potentially targetable receptor tyrosine kinase fusions in diverse cancers by DNA-based profiling","volume":"6","author":"Wang","year":"","journal-title":"NPJ Precis. Oncol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41698-021-00206-y","article-title":"Genomic context of NTRK1\/2\/3 fusion-positive tumours from a large real-world population","volume":"5","author":"Westphalen","year":"2021","journal-title":"NPJ Precis. Oncol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.1007\/s12253-019-00685-2","article-title":"Methods for identifying patients with tropomyosin receptor kinase (TRK) fusion cancer","volume":"26","author":"Wong","year":"2020","journal-title":"Pathol. Oncol. Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"105369","DOI":"10.1016\/j.oraloncology.2021.105369","article-title":"Targeted DNA profiling and the prevalence of NTRK aberrations in Chinese patients with head and neck cancer","volume":"119","author":"Xu","year":"2021","journal-title":"Oral Oncol."}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1550706\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T11:44:29Z","timestamp":1746186269000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2025.1550706\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,2]]},"references-count":43,"alternative-id":["10.3389\/fgene.2025.1550706"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2025.1550706","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,2]]},"article-number":"1550706"}}