ETV6

Overview

ETV6 encodes an ETS-family transcriptional repressor. The ETV6-NTRK3 fusion is the canonical driver of infantile fibrosarcoma (IFS) and is present in ~90% of cases. ETV6-NTRK3 status, assessed by FISH or RNA fusion testing, is a key diagnostic criterion and biomarker for larotrectinib sensitivity.

Alterations observed in the corpus

  • ETV6-NTRK3 fusion was expected (absent by FISH) in SARC0127, a suspected infantile fibrosarcoma (IFS) case in the UCLA sarcoma patient-derived tumor organoid (PDTO) study (n=194 specimens, 126 patients). The PDTO was resistant to larotrectinib, the TRK inhibitor indicated for NTRK-fusion-positive tumors; negative ETV6 FISH and larotrectinib resistance jointly led to reclassification as high-grade spindle cell/sclerosing rhabdomyosarcoma (SCSRMS), illustrating the diagnostic utility of functional PDTO screening as an orthogonal tool to pathology PMID:39305899.
  • ETV6 was identified among recurrent genomic alterations in prostate cancer in an integrative genomic profiling study PMID:20579941
  • ETV6 is recurrently mutated in DLBCL by whole-exome sequencing of 55 tumors (MutSig analysis, Broad Institute) PMID:22343534
  • Fusion events observed in TNBC WGS cohort (BCCRC, 65 tumors) PMID:22495314
  • Recurrently mutated in pediatric ALL (St. Jude WGS/WES, 44 tumors); ETV6-RUNX1 fusions detected in B-ALL cases PMID:23334668
  • Co-deleted with ETV3 and CDKN1B in a 25-rearrangement chromoplexy chain in prostate cancer PMID:23622249
  • ETV6/NTRK3 fusion detected in papillary thyroid carcinoma (PTC); part of 6/484 (1.2%) NTRK1/3 fusions combined; fusion is BRS-neutral (neither BVL nor RL phenotype). PMID:25417114
  • Implicated in PCNSL via focal amplification or homozygous deletion event PMID:25991819
  • ETV6-NTRK3 fusion identified in 2 tumors initially diagnosed as acinic cell carcinoma, reclassifying them as mammary analogue secretory carcinoma (MASC); both patients responded to TRK inhibitor on a basket trial PMID:27442865
  • Preferentially mutated in ABC-DLBCL; ETV6 mutations in DLBCL are ABC-subtype-enriched in the comprehensive genetic and functional driver analysis PMID:28985567
  • ETV6-NTRK3 fusion identified in MSI-H colorectal cancer (8% MSI-H vs 1% MSS NTRK fusion rate overall); ETV6-NTRK3 is a known oncogenic fusion relevant to TRK inhibitor therapy PMID:29316426

Cancer types (linked)

Co-occurrence and mutual exclusivity

  • ETV6-NTRK3 fusion is mutually exclusive with the SCSRMS diagnosis; its absence is necessary for this reclassification PMID:39305899.

Therapeutic relevance

  • NTRK inhibitor (larotrectinib) response depends on the presence of NTRK3 fusion; PDTO resistance to larotrectinib in the absence of ETV6-NTRK3 fusion correctly predicted non-response and prompted timely diagnostic reclassification (within one week vs 18 days for pathology) PMID:39305899.

Open questions

  • Whether other NTRK3 fusion partners (not ETV6) might explain rare PDTO larotrectinib resistance in IFS-like tumors was not investigated in this case.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:27442865

This page was processed by entity-page-writer on 2026-05-15. - PMID:28985567

This page was processed by wiki-cli on 2026-05-15. - PMID:29316426

This page was processed by wiki-cli on 2026-05-15.