TRK expressions and NTRK rearrangements in Pediatric Tumors

TRK expressions and NTRK rearrangements in Pediatric Tumors | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article TRK expressions and NTRK rearrangements in Pediatric Tumors Hiba Altarrah, Amal Alodini, Asrar Alzaher, Omar Chamdine, Qasim Alharbi, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7527708/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Neurotrophic tyrosine receptor kinase (NTRK) genes that include NTRK1, NTRK2, NTRK3 and express TRKA, TRKB, TRKC proteins, respectively, are oncogenic drivers in distinct types of cancer. NTRK fusions with other genes result in constitutively active TRK protein expressions that enhance tumor progression. NTRK fusions were found in more than twenty-five types of cancer. However, the incidence of NTRK fusions is frequently found in pediatric tumors compared to adults. Infantile fibrosarcoma, CNS cancers, and congenital mesoblastic nephroma are the most common types of pediatric cancer that harbor NTRK fusions. NTRK3 fusion is the most common type found in infantile fibrosarcoma, while NTRK2 is almost exclusively seen in CNS tumors. The FDA has approved Larotrectinib (Vitrakvi), and Entrectinib (Rozlytrek) targeted therapy for tumors harboring NTRK fusions. Larotrectinib and Entrectinib demonstrated selective inhibition of TRKA, TRKB, and TRKC expressions. Objective: To characterize NTRK fusions in diverse types of pediatric cancers and describe the treatment management and the response for each case. Design/Method: Here, we present five cases of pediatric cancers that present TRK proteins. The clinical investigations of these cases confirmed NTRK fusion using molecular assay and/or the immunohistochemistry method. Three out of five cases were treated with NTRK inhibitors. The cancer prognosis was monitored to assess tumor regression using clinical assessment and MRI. Results: In this study of five pediatric cases, TRK expression was identified through immunohistochemistry, and four of these cases demonstrated NTRK fusions detected by molecular assays. The first case involved an infantile fibrosarcoma with an ETV6-NTRK3 fusion. The second case was another infantile fibrosarcoma with an LMNA-NTRK1 fusion, while the third case was a low-grade glioma (LGG) with an AGAP1-NTRK2 fusion. The fourth case, an infantile fibrosarcoma, was initially positive for TRK expression by immunohistochemistry, but molecular testing showed no evidence of an NTRK fusion, leading to the exclusion of TRK inhibitor treatment. The fifth case also involved an infantile fibrosarcoma with a TMP3-NTRK1 fusion. Treatment outcomes varied: all cases with molecularly proven NTRK fusions who had access to NTRK inhibitors responded to treatment. Two cases did not have access to NTRK inhibitors at the time of surgery; one of these had a late metastatic relapse, started treatment at relapse, and responded well to NTRK inhibition, remaining in remission as long as the therapy was continued. Conclusion: TRK expression was identified in pediatric sarcoma and low-grade glioma with different NTRK rearrangements. NTRK1 and NTRK3 fusions were detected in infantile fibrosarcoma, whereas the NTRK2 fusion was seen in CNS tumor. Pan-TRK histological expression proved to be a helpful screening tool before molecular testing for NTRK genes. However, it has limited accuracy in determining NTRK fusions. Interestingly, the treatment with TRK inhibitors for patients that have molecular NTRK fusions presented rapid tumor response and tumor regression. Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7527708","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":510150960,"identity":"65d30b0a-6bcb-4fa4-a36f-2ccc1815177b","order_by":0,"name":"Hiba Altarrah","email":"","orcid":"","institution":"King Fahad Specialist Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hiba","middleName":"","lastName":"Altarrah","suffix":""},{"id":510150962,"identity":"f0424632-d57d-49bb-b419-6f8059a5417d","order_by":1,"name":"Amal Alodini","email":"","orcid":"","institution":"Imam Abdulrahman Bin Faisal 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Specialist Hospital","correspondingAuthor":true,"prefix":"","firstName":"Kholoud","middleName":"","lastName":"Alwosaibai","suffix":""}],"badges":[],"createdAt":"2025-09-03 13:53:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7527708/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7527708/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90695199,"identity":"f7380027-42d6-439f-9a82-a354f31ee0fc","added_by":"auto","created_at":"2025-09-05 19:54:55","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1082073,"visible":true,"origin":"","legend":"","description":"","filename":"NTRKmanuscriptupdated3sepeditedbyALLforsubmessiontoBMCcancer1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7527708/v1_covered_d5eb75f7-61c0-4ca0-b7a6-919f580f20f7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"TRK expressions and NTRK rearrangements in Pediatric Tumors","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7527708/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7527708/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNeurotrophic tyrosine receptor kinase (NTRK) genes that include NTRK1, NTRK2, NTRK3 and express TRKA, TRKB, TRKC proteins, respectively, are oncogenic drivers in distinct types of cancer.\u003c/p\u003e\n\u003cp\u003eNTRK fusions with other genes result in constitutively active TRK protein expressions that enhance tumor progression. NTRK fusions were found in more than twenty-five types of cancer. However, the incidence of NTRK fusions is frequently found in pediatric tumors compared to adults. Infantile fibrosarcoma, CNS cancers, and congenital mesoblastic nephroma are the most common types of pediatric cancer that harbor NTRK fusions. NTRK3 fusion is the most common type found in infantile fibrosarcoma, while NTRK2 is almost exclusively seen in CNS tumors.\u003c/p\u003e\n\u003cp\u003eThe FDA has approved Larotrectinib (Vitrakvi), and Entrectinib (Rozlytrek) targeted therapy for tumors harboring NTRK fusions. Larotrectinib and Entrectinib demonstrated selective inhibition of TRKA, TRKB, and TRKC expressions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo characterize NTRK fusions in diverse types of pediatric cancers and describe the treatment management and the response for each case.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDesign/Method:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHere, we present five cases of pediatric cancers that present TRK proteins. The clinical investigations of these cases confirmed NTRK fusion using molecular assay and/or the immunohistochemistry method. Three out of five cases were treated with NTRK inhibitors. The cancer prognosis was monitored to assess tumor regression using clinical assessment and MRI.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study of five pediatric cases, TRK expression was identified through immunohistochemistry, and four of these cases demonstrated NTRK fusions detected by molecular assays. The first case involved an infantile fibrosarcoma with an ETV6-NTRK3 fusion. The second case was another infantile fibrosarcoma with an LMNA-NTRK1 fusion, while the third case was a low-grade glioma (LGG) with an AGAP1-NTRK2 fusion. The fourth case, an infantile fibrosarcoma, was initially positive for TRK expression by immunohistochemistry, but molecular testing showed no evidence of an NTRK fusion, leading to the exclusion of TRK inhibitor treatment. The fifth case also involved an infantile fibrosarcoma with a TMP3-NTRK1 fusion. Treatment outcomes varied: all cases with molecularly proven NTRK fusions who had access to NTRK inhibitors responded to treatment. Two cases did not have access to NTRK inhibitors at the time of surgery; one of these had a late metastatic relapse, started treatment at relapse, and responded well to NTRK inhibition, remaining in remission as long as the therapy was continued.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTRK expression was identified in pediatric sarcoma and low-grade glioma with different NTRK rearrangements. NTRK1 and NTRK3 fusions were detected in infantile fibrosarcoma, whereas the NTRK2 fusion was seen in CNS tumor. Pan-TRK histological expression proved to be a helpful screening tool before molecular testing for NTRK genes. However, it has limited accuracy in determining NTRK fusions. Interestingly, the treatment with TRK inhibitors for patients that have molecular NTRK fusions presented rapid tumor response and tumor regression.\u003c/p\u003e","manuscriptTitle":"TRK expressions and NTRK rearrangements in Pediatric Tumors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-05 19:30:47","doi":"10.21203/rs.3.rs-7527708/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3fd60eb9-5781-4244-b2ae-2d56ad694321","owner":[],"postedDate":"September 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-05T19:30:49+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-05 19:30:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7527708","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7527708","identity":"rs-7527708","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}