HMGA1

Overview

HMGA1 (High Mobility Group AT-Hook 1) encodes an architectural chromatin-binding protein that modulates transcription by altering chromatin structure. It is a well-established oncogene in multiple tumor types and has now been identified as a dominant driver in endometrial polyps via non-fusion enhancer hijacking rather than classic gene fusion mechanisms. HMGA1 rearrangements lead to stromal overexpression of the protein and downstream upregulation of PLAG1 and other transcriptional targets, repositioning endometrial polyps as stromal-driven neoplasms.

Alterations observed in the corpus

  • Chromosomal rearrangements upstream (12/14 rearrangements), in the 3’UTR (2/14), or downstream (1/14) of HMGA1 in 14/23 endometrial polyps (WGS discovery cohort); mean rearrangement VAF 0.24 (range 0.06–0.43); recurrent partners include the 7p15.2 enhancer ENSR00001272277, LRMDA (10q22.3), RAD51B (14q24.1), and TRAF3IP2 (6q21); one sample also carried a somatic missense c.268C>G p.(Leu90Val); result is HMGA1 mRNA and protein overexpression in the stromal compartment PMID:28445112

Cancer types (linked)

  • UCEC (Endometrial Carcinoma / Endometrial Polyps): HMGA1 rearrangements are the most common alteration in endometrial polyps (61%, 14/23 polyps), establishing stromal enhancer hijacking as the dominant initiating event; co-occurring low-VAF mutations in KRAS, PIK3CA, PIK3R1, PTEN support a subset of polyps as precursor lesions for endometrial carcinoma PMID:28445112
  • ULM (Uterine Leiomyoma): HMGA1 alterations parallel those found in uterine leiomyoma biology, suggesting shared HMGA-pathway mechanisms across gynecological stromal neoplasms PMID:28445112

Co-occurrence and mutual exclusivity

  • HMGA1 and HMGA2 rearrangements share the same partner repertoire and typically occur in distinct polyps (HMGA2-rearranged in 4/23 polyps); downstream target PLAG1 is transcriptionally upregulated (log2FC 3.22) in HMGA1-rearranged polyps without DNA-level PLAG1 alterations PMID:28445112
  • ZMAT3 is the top differentially upregulated gene in HMGA-aberrant polyps PMID:28445112

Therapeutic relevance

  • No specific drug targeting HMGA1 is proposed for current clinical use; authors suggest HMGA-targeted therapy (e.g., HMGA2 gene silencing explored in ovarian carcinoma) could in principle be repurposed across HMGA-driven gynecological lesions PMID:28445112

Open questions

  • Some samples showed strong HMGA1 staining without a WGS-detected rearrangement and vice versa, possibly due to cellular composition, FFPE artifact, or short-read SV sensitivity limits PMID:28445112
  • The 7p15.2 enhancer ENSR00001272277 has no known target gene in this tissue; the proposed enhancer-hijacking mechanism is plausible but not yet functionally proven PMID:28445112

Sources

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