HAND1 and BARX1 Act as Transcriptional and Anatomic Determinants of Malignancy in Gastrointestinal Stromal Tumor

Clin Cancer Res. 2021 Mar 15;27(6):1706-1719. doi: 10.1158/1078-0432.CCR-20-3538. Epub 2021 Jan 15.


Purpose: Gastrointestinal stromal tumor (GIST) arises from interstitial cells of Cajal (ICC) or their precursors, which are present throughout the gastrointestinal tract. Although gastric GIST is commonly indolent and small intestine GIST more aggressive, a molecular understanding of disease behavior would inform therapy decisions in GIST. Although a core transcription factor (TF) network is conserved across GIST, accessory TFs HAND1 and BARX1 are expressed in a disease state-specific pattern. Here, we characterize two divergent transcriptional programs maintained by HAND1 and BARX1, and evaluate their association with clinical outcomes.

Experimental design: We evaluated RNA sequencing and TF chromatin immunoprecipitation with sequencing in GIST samples and cultured cells for transcriptional programs associated with HAND1 and BARX1. Multiplexed tissue-based cyclic immunofluorescence and IHC evaluated tissue- and cell-level expression of TFs and their association with clinical factors.

Results: We show that HAND1 is expressed in aggressive GIST, modulating KIT and core TF expression and supporting proliferative cellular programs. In contrast, BARX1 is expressed in indolent and micro-GISTs. HAND1 and BARX1 expression were superior predictors of relapse-free survival, as compared with standard risk stratification, and they predict progression-free survival on imatinib. Reflecting the developmental origins of accessory TF programs, HAND1 was expressed solely in small intestine ICCs, whereas BARX1 expression was restricted to gastric ICCs.

Conclusions: Our results define anatomic and transcriptional determinants of GIST and molecular origins of clinical phenotypes. Assessment of HAND1 and BARX1 expression in GIST may provide prognostic information and improve clinical decisions on the administration of adjuvant therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Follow-Up Studies
  • Gastrointestinal Neoplasms / genetics
  • Gastrointestinal Neoplasms / metabolism
  • Gastrointestinal Neoplasms / pathology*
  • Gastrointestinal Stromal Tumors / genetics
  • Gastrointestinal Stromal Tumors / metabolism
  • Gastrointestinal Stromal Tumors / pathology*
  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Humans
  • Prognosis
  • RNA-Seq
  • Survival Rate
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcriptome*
  • Tumor Cells, Cultured


  • BARX1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • Biomarkers, Tumor
  • Homeodomain Proteins
  • Transcription Factors
  • helix-loop-helix protein, eHAND