{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T06:30:06Z","timestamp":1766989806157,"version":"3.48.0"},"reference-count":30,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,28]],"date-time":"2025-12-28T00:00:00Z","timestamp":1766880000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["24K11939"],"award-info":[{"award-number":["24K11939"]}]},{"name":"Japan Society for the Promotion of Science (JSPS) KAKENHI","award":["21K08758"],"award-info":[{"award-number":["21K08758"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neurotrophic tyrosine receptor kinase (NTRK) fusions function as oncogenes and have been targeted by TRK inhibitors with excellent clinical outcomes. The international expert consensus recommends immunohistochemical (IHC) screening for TRK protein followed by next generation sequencing (NGS) to measure expression of NTRK fusions for tumors with low NTRK fusion expression. To confirm the clinical utility of this recommendation in esophageal and gastric cancers, total TRK protein expression was measured by IHC using anti-pan-TRK antibody in 254 esophageal squamous cell carcinoma (ESCC) and 401 gastric adenocarcinoma (GA) samples. Subsequently, DNA-based NGS and fluorescence in situ hybridization (FISH) were performed for tumors expressing TRK to measure NTRK fusion expression. Further, expression of NTRK fusions was evaluated in esophageal and gastric cancers using public databases. IHC staining revealed TRK was expressed in 10 out of 254 ESCC and 0 out of 401 GC cases. NGS and FISH analyses were performed for 10 TRK positive ESCC cases, identifying that none of these cases harbored NTRK fusions. In silico analyses further confirmed that NTRK fusions are rarely present in esophageal and gastric cancers. IHC screening for TRK protein is recommended to detect NTRK fusions, but this method may include many false-positives cases based on the sequencing analysis.<\/jats:p>","DOI":"10.3390\/ijms27010336","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T06:25:51Z","timestamp":1766989551000},"page":"336","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of NTRK Fusions Detection Method in Esophageal Squamous Cell Carcinoma and Gastric Adenocarcinoma"],"prefix":"10.3390","volume":"27","author":[{"given":"Tomoyuki","family":"Momma","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-3520","authenticated-orcid":false,"given":"Motonobu","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan"},{"name":"Department of Cancer Genome Medicine, Fukushima Medical University Hospital, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shotaro","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan"},{"name":"Department of Multidisciplinary Treatment of Cancer and Regional Medical Support, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsuharu","family":"Saito","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erika","family":"Machida","sequence":"additional","affiliation":[{"name":"Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"name":"Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama 330-8503, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken","family":"Miyabe","sequence":"additional","affiliation":[{"name":"Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2729-7284","authenticated-orcid":false,"given":"Yusuke","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Esophageal Surgery, Akita University Hospital, Akita 010-8543, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Hanayama","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0966-4746","authenticated-orcid":false,"given":"Hirokazu","family":"Okayama","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zenichiro","family":"Saze","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2565-154X","authenticated-orcid":false,"given":"Kosaku","family":"Mimura","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan"},{"name":"Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoto","family":"Tsuchiya","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Carcinogenesis, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"name":"Clinical Cancer Research Division, Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, Kamakura 247-8533, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8776-9004","authenticated-orcid":false,"given":"Akiteru","family":"Goto","sequence":"additional","affiliation":[{"name":"Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita 010-8543, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5821-7400","authenticated-orcid":false,"given":"Kouya","family":"Shiraishi","sequence":"additional","affiliation":[{"name":"Division of Genome Biology, National Cancer Center Research Institute, Tokyo 104-0045, Japan"},{"name":"Department of Clinical Genomics, National Cancer Center Research Institute, Tokyo 104-0045, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Kono","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","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":"ref_2","doi-asserted-by":"crossref","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":"ref_3","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1111\/cas.12941","article-title":"Gene aberrations for precision medicine against lung adenocarcinoma","volume":"107","author":"Saito","year":"2016","journal-title":"Cancer Sci."},{"key":"ref_4","doi-asserted-by":"crossref","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. 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Pathol."},{"key":"ref_8","doi-asserted-by":"crossref","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":"ref_9","doi-asserted-by":"crossref","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":"2","author":"Okamura","year":"2018","journal-title":"JCO Precis. Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","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":"ref_11","doi-asserted-by":"crossref","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":"ref_12","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.annonc.2020.03.299","article-title":"JSCO-ESMO-ASCO-JSMO-TOS: International expert consensus recommendations for tumour-agnostic treatments in patients with solid tumours with microsatellite instability or NTRK fusions","volume":"31","author":"Yoshino","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"152662","DOI":"10.1016\/j.prp.2019.152662","article-title":"Analysis of NTRK expression in gastric and esophageal adenocarcinoma (AGE) with pan-TRK immunohistochemistry","volume":"215","author":"Arnold","year":"2019","journal-title":"Pathol. Res. Pract."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Gluckstein, M.I., Dintner, S., Miller, S., Vlasenko, D., Schenkirsch, G., Agaimy, A., Markl, B., and Grosser, B. (2022). ALK, NUT, and TRK Do Not Play Relevant Roles in Gastric Cancer-Results of an Immunohistochemical Study in a Large Series. Diagnostics, 12.","DOI":"10.3390\/diagnostics12020429"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2923","DOI":"10.1038\/bjc.2014.228","article-title":"Tropomyosin-related receptor kinase B at the invasive front and tumour cell dedifferentiation in gastric cancer","volume":"110","author":"Tanaka","year":"2014","journal-title":"Br. J. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s12094-015-1407-7","article-title":"Prognostic value of tropomyosin-related kinases A, B, and C in gastric cancer","volume":"18","author":"Kamiya","year":"2016","journal-title":"Clin. Transl. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1038\/s41598-021-81667-w","article-title":"PD-L1 overexpression in EBV-positive gastric cancer is caused by unique genomic or epigenomic mechanisms","volume":"11","author":"Nakano","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"445","DOI":"10.3892\/ol.2021.12706","article-title":"Stromal expression of cancer-associated fibroblast-related molecules, versican and lumican, is strongly associated with worse relapse-free and overall survival times in patients with esophageal squamous cell carcinoma","volume":"21","author":"Yamauchi","year":"2021","journal-title":"Oncol. Lett."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1158\/1541-7786.MCR-20-0917","article-title":"Neoadjuvant Chemotherapy Induces IL34 Signaling and Promotes Chemoresistance via Tumor-Associated Macrophage Polarization in Esophageal Squamous Cell Carcinoma","volume":"19","author":"Nakajima","year":"2021","journal-title":"Mol. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"6769","DOI":"10.1038\/s41598-019-43293-5","article-title":"Prognostic role of ARID1A negative expression in gastric cancer","volume":"9","author":"Ashizawa","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1111\/cas.13969","article-title":"Feasibility and utility of a panel testing for 114 cancer-associated genes in a clinical setting: A hospital-based study","volume":"110","author":"Sunami","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1016\/j.jmoldx.2019.03.008","article-title":"Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy","volume":"21","author":"Hsiao","year":"2019","journal-title":"J. Mol. Diagn. JMD"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41379-019-0324-7","article-title":"NTRK fusion detection across multiple assays and 33,997 cases: Diagnostic implications and pitfalls","volume":"33","author":"Solomon","year":"2020","journal-title":"Mod. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1007\/s10120-020-01061-9","article-title":"The first case of gastric carcinoma with NTRK rearrangement: Identification of a novel ATP1B-NTRK1 fusion","volume":"23","author":"Ishikawa","year":"2020","journal-title":"Gastric Cancer"},{"key":"ref_25","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"39028","DOI":"10.18632\/oncotarget.5494","article-title":"NTRK1 rearrangement in colorectal cancer patients: Evidence for actionable target using patient-derived tumor cell line","volume":"6","author":"Lee","year":"2015","journal-title":"Oncotarget"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1097\/PAS.0000000000001062","article-title":"Pan-Trk Immunohistochemistry Identifies NTRK Rearrangements in Pediatric Mesenchymal Tumors","volume":"42","author":"Rudzinski","year":"2018","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","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":"Consortium","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1038\/nature13480","article-title":"Comprehensive molecular characterization of gastric adenocarcinoma","volume":"513","year":"2014","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Pasini, L., Re, A., Tebaldi, T., Ricci, G., Boi, S., Adami, V., Barbareschi, M., and Quattrone, A. (2015). TrkA is amplified in malignant melanoma patients and induces an anti-proliferative response in cell lines. BMC Cancer, 15.","DOI":"10.1186\/s12885-015-1791-y"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/336\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T06:27:07Z","timestamp":1766989627000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/336"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,28]]},"references-count":30,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27010336"],"URL":"https:\/\/doi.org\/10.3390\/ijms27010336","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,28]]}}}