NTRK1

Overview

NTRK1 encodes the TrkA receptor tyrosine kinase. Oncogenic NTRK1 fusions are actionable with TRK inhibitors. In the corpus it appears as a rare fusion in histiocytosis.

Alterations observed in the corpus

  • PRDX1-NTRK1 fusion identified in one histiocytosis patient, detected only by targeted RNA sequencing in the Make-an-IMPACT rare-cancer program PMID:36862133.
  • NTRK1 fusions identified as driver fusions in patients who subsequently acquired BRAF fusions as resistance mechanism to prior therapy; NTRK1 fusions identified in the tumor-agnostic BRAF fusion cohort across 52 histologies (N=833) PMID:38922339.
  • NTRK1 (TRKA) is a marker of the noradrenergic NOR clusters (nC5/nC7/nC8/nC9) enriched in low-risk neuroblastoma; validated as a favorable-outcome biomarker at the single-cell level by RNAscope ISH in both low-risk and high-risk tumor samples; NOR cluster gene signatures correlated with better survival in the 498-patient SEQC cohort (Kaplan-Meier, Bonferroni-corrected p <0.01) PMID:34493726.
  • In a MYCN-amplified high-risk tumor (K10), RNAscope showed NTRK1+/TH+/NTRK2− cells with enlarged nuclei (possibly differentiating) surrounded by NTRK1−/NTRK2+ undifferentiated cells, confirming single-cell intratumoral NTRK1/NTRK2 mutual exclusivity PMID:34493726.
  • NTRK1 fusions (expected canonical ETV6–NTRK3 in IFS; FISH-negative result led to reclassification of SARC0127 as SCSRMS): NTRK1/NTRK2/NTRK3 listed as actionable fusion targets evaluated in 194-specimen sarcoma PDTO platform; larotrectinib resistance and reclassification highlight importance of orthogonal genomic testing. PMID:39305899
  • Oncogenic NTRK1 fusions listed as OncoKB level 1 or 2 biomarkers (~10% of all patients with pan-PDAC actionability) in the MSK 2,336-patient PDAC cohort. PMID:39753968
  • Part of NTRK family (NTRK1/2/3) with 20 total mutations in 188 LUAD tumours, 7 in kinase domains; recurrent somatic mutations establish NTRK1 as a LUAD candidate driver. PMID:18948947
  • NTRK1 LMNA::NTRK1 fusion in 1 GBC patient (OncoKB level 1; FDA-recognized biomarker predictive of response to entrectinib/larotrectinib) PMID:36228155
  • Discussed as analogous context: NTRK1 fusions in other cancers provide precedent for the NTRK2 kinase-domain-retaining fusions newly described in pilocytic astrocytoma PMID:23817572
  • NTRK1 fusions detected in PTC; ETV6/NTRK3 and RBPMS/NTRK3 fusions among 1.2% (6/484) NTRK events; fusions were BRS-neutral in the BVL/RL classification PMID:25417114
  • NTRK1/2/3 fusions reported in ~0.2% of CCA overall, up to 3.6% of intrahepatic CCA; targetable with entrectinib and larotrectinib PMID:25526346
  • MAPK-pathway alteration enriched in PA-like LGG (52%) and LGm6-GBM (32%) subtypes in diffuse glioma PMID:26824661
  • NTRK1 fusions in thyroid cancer could not be assessed because the IMPACT 341-gene panel does not cover NTRK1 intronic regions; explicitly flagged as a detection gap in the study of PDTC and ATC PMID:26878173
  • NTRK1 fusions identified in pan-lung cancer TCGA analysis (n=1144) in lung adenocarcinoma PMID:27158780
  • Mentioned as a rare fusion target in young lung cancer (YLC) with scarce age-stratified frequency data PMID:27346245
  • Fusions present in 8% of MSI-H vs 1% of MSS mCRC; specific fusions: LMNA-NTRK1 (3 cases: 1 MSS, 2 MSI-H), TPM3-NTRK1; TRK-inhibitor candidates in MSI-H mCRC PMID:29316426
  • Among the top recurrent 3’-kinase tyrosine kinases enriched in THCA (thyroid carcinoma) fusions in pan-cancer RNA-seq analysis of 9,624 TCGA samples; 94% of THCA kinase fusions involve 3’-enriched kinases including NTRK1, NTRK3, and BRAF. PMID:29617662

Cancer types (linked)

  • Histiocytosis (LCH, ECD) — actionable fusion detected via RNA-seq PMID:36862133.
  • Pan-cancer — NTRK1 fusions are driver events that can be superseded by acquired BRAF fusions as a resistance mechanism at progression PMID:38922339.
  • NBL — NTRK1/TRKA marks low-risk noradrenergic tumor clusters; high expression correlates with favorable prognosis; mutually exclusive with NTRK2/TRKB-high high-risk identity PMID:34493726.

Co-occurrence and mutual exclusivity

  • Mutually exclusive with NTRK2 at the single-cell level in neuroblastoma; NTRK1+/NTRK2− identifies the low-risk noradrenergic identity and NTRK1−/NTRK2+ identifies the high-risk undifferentiated identity PMID:34493726.

Therapeutic relevance

  • NTRK1 fusions are actionable, but this specific patient’s treatment outcome is not detailed in the paper PMID:36862133.
  • NTRK1/TRKA high expression in neuroblastoma identifies low-risk patients who may not require intensive therapy; NTRK1 vs NTRK2 expression ratio at the single-cell level provides a transcriptional basis for the clinical risk dichotomy PMID:34493726.

Open questions

Sources

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