Stains & CD markers
HMGA2


Last author update: 11 June 2024
Last staff update: 11 June 2024

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PubMed Search: HMGA2

Pamela Wirth, Ph.D.
Page views in 2024 to date: 915
Cite this page: Wirth P. HMGA2. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/stainsHMGA2.html. Accessed June 16th, 2024.
Definition / general
  • Transcription factor involved in maintenance and regulation of replication, recombination, transcription and DNA repair that is strongly upregulated in many cancers
Essential features
  • HMGA 2 (high mobility group AT hook 2) belongs to nonhistone chromosomal high mobility group protein family
    • Consists of 4 proteins: HMGA1a, HMGA1b, HMGA1c and HMGA2
  • Highly expressed in embryonic stem cells during embryogenesis
  • Highly expressed in many human malignancies
Terminology
  • HMG1C
Pathophysiology
  • Involved in maintenance and regulation of replication, recombination, transcription and DNA repair
  • Activates signaling via MAPK / ERK, TGFβ / Smad, PI3K / Akt / mTor, NFkβ and STAT3 pathways
  • Transcription factor that increases cancer cell proliferation by inhibiting apoptosis and cell cycle entry
  • Promoter of epithelial to mesenchymal transition (EMT) (Genes (Basel) 2021;12:269)
  • Enhances expression of EMT regulators such as Snail, Twist, Slug and ZEB1 resulting in the downregulation of E-cadherin and upregulation of vimentin (J Cancer Res Clin Oncol 2021;147:3313)
Diagrams / tables

Images hosted on other servers:
HMGA2 activation leading to proliferation and apoptosis

HMGA2 activation
leading to
proliferation
and apoptosis

Clinical features
  • Can be part of the panel used for differential diagnosis between benign thyroid lesions (such as nodular goiter) and malignant thyroid tumors (such as papillary thyroid carcinoma)
  • HMGA2 positivity can be seen in some soft tissue subtypes like lipomas or aggressive fibromatosis
    • Helpful for the distinction of normal adipose tissue (negative) from well differentiated lesions (positive)
    • Expressed almost exclusively by atypical lipomatous tumor / well differentiated and dedifferentiated liposarcomas
    • HMGA2 is expressed in benign fibrous histiocytoma, nodular fasciitis and vulvovaginal benign mesenchymal tumors (Mod Pathol 2010;23:1657)
Interpretation
  • Nuclear expression in most tissues
Uses by pathologists
  • Helpful for the distinguishing normal adipose tissue from well differentiated adipose lesions
  • Useful for the diagnosis of benign fibrous histiocytoma, nodular fasciitis and vulvovaginal benign mesenchymal tumors (Mod Pathol 2010;23:1657)
  • High nuclear expression is associated with tumor progression, metastasis and resistance to chemotherapy in various cancers (Sci Rep 2018;8:14008)
Prognostic factors
  • Overexpression is an unfavorable prognostic marker in urothelial cancer, head and neck cancer, lung cancer, ovarian cancer and metastatic breast cancer (Clin Cancer Res 2011;17:2570)
  • Associated with progression, metastasis and chemotherapy resistance in pancreatic ductal carcinoma (Sci Rep 2018;8:14008)
  • Associated with metastasis and reduced survival for patients with stage 3 and 4 colorectal cancer
Microscopic (histologic) images

Contributed by Pamela Wirth, Ph.D. (source: Human Protein Atlas)
Seminoma

Seminoma

Papillary adenocarcinoma

Papillary adenocarcinoma

Stomach adenocarcinoma

Stomach adenocarcinoma

Head and neck carcinoma

Head and neck carcinoma

Urinary bladder

Urinary bladder

Pancreas

Pancreas

Positive staining - normal
Positive staining - disease
Negative staining
  • Normal adipose tissue (Mod Pathol 2010;23:1657)
  • 15% of non-well differentiated liposarcomas / dedifferentiated liposarcomas may show HMGA2 protein expression (Mod Pathol 2010;23:1657)
  • HMGA2 levels are undetectable in most adult cells; however, low levels may be present in lungs, kidneys and benign mesenchymal tumor tissues (BMC Biology 2022;20:171)
Molecular / cytogenetics description
Sample pathology report
  • Core biopsy, pancreas:
    • Poorly differentiated pancreatic ductal adenocarcinoma (see comment)
    • Comment: Core biopsy of the pancreas showed irregular glands embedded within a prominent desmoplastic stroma containing a mixture of dense collagen, fibroblasts and inflammatory cells. Immunohistochemistry was positive for CK7, CK19, CEA, MUC1 and HMGA2. These findings are consistent for poorly differentiated pancreatic ductal adenocarcinoma.
Board review style question #1

Which of the following statements about HMGA2 is correct?

  1. HMGA2 enhances the proliferation of cancer cells by inhibiting the cell cycle and promoting apoptosis
  2. HMGA2 is downregulated in many human malignancies
  3. HMGA2 is primarily expressed in adult tissues and is absent in fetal tissues
  4. HMGA2 is primarily expressed in the cytoplasm and membrane of normal and neoplastic cells
Board review style answer #1
A. HMGA2 enhances the proliferation of cancer cells by inhibiting the cell cycle and promoting apoptosis. This is supported by its role as a transcription factor that promotes tumor growth and survival along with its documented upregulation in many cancer types. Answer C is incorrect because HMGA2 is widely expressed in undifferentiated cells during embryogenesis but declines as fetal development progresses with very limited expression in adult tissues. Answers B and D are incorrect because HMGA2 activates many signaling pathways related to growth and differentiation and is highly expressed in the nucleus of many cancer types as shown in the associated image of seminoma.

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Reference: HMGA2
Board review style question #2
HMGA2 gene alterations are associated with which of the following conditions?

  1. Beckwith-Wiedemann syndrome
  2. Laron syndrome
  3. Silver-Russell syndrome
  4. SOX2 anophthalmia syndrome
Board review style answer #2
C. Silver-Russell syndrome (SRS). SRS, a condition of delayed growth, has been associated with genetic variants in HMGA2 due to microdeletions in chromosomes 12p14. Answer D is incorrect because although SOX2 has similar functions to HMGA2 in the maintenance of embryonic and neural stem cells, anophthalmia syndrome is not a condition associated with HMGA2. Answer A is incorrect because Beckwith-Wiedemann syndrome is a growth affecting disorder commonly involving mutations to the CDKN1C gene but is not associated with mutations in HMGA2. Answer B is incorrect because although Laron syndrome is a condition characterized by growth abnormalities, it is caused by mutations in the growth hormone receptor gene.

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Reference: HMGA2
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