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Stains & CD markers
HMGA2

Author: Pamela Wirth, Ph.D.

Editorial Board Members: Christian M. Schürch, M.D., Ph.D., Nasir Ud Din, M.B.B.S.

Last author update: 11 June 2024

Last staff update: 11 June 2024

Copyright: 2021-2025, PathologyOutlines.com, Inc.

PubMed Search: HMGA2

Table of Contents

Cite this page: Wirth P. HMGA2. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsHMGA2.html. Accessed January 3rd, 2025.

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

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)
- High expression in papillary carcinoma and anaplastic carcinoma; negative in normal thyroid (Eur J Cancer 2008;44:1015)
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
- Some cytoplasmic expression is correlated with lymph vessel and venous invasion in pancreatic ductal adenocarcinoma (J Cancer Res Clin Oncol 2021;147:3313)
- May show cytoplasmic expression in luminal A and triple negative breast cancer, which is associated with a more favorable overall survival (Int J Biol Markers 2020;35:20)

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

Papillary adenocarcinoma

Stomach adenocarcinoma

Head and neck carcinoma

Urinary bladder

Pancreas

Positive staining - normal

Many fetal tissues express HMGA2, especially kidney, liver and uterus (Atlas Genet Cytogenet Oncol Haematol: HMGA2 (High Mobility Group AT-Hook 2) [Accessed 19 April 2024])

Positive staining - disease

Positive staining in many carcinomas including those found in breast, pancreas, ovary, lung, colon, nerve system and oral cavity (squamous cell carcinomas) (Atlas Genet Cytogenet Oncol Haematol: HMGA2 (High Mobility Group AT-Hook 2) [Accessed 19 April 2024])
Strong protein expression in pleomorphic adenomas
- Highly specific (92%) but low sensitivity (30%) (Histopathology 2017;71:511)
Helpful for distinguishing normal adipose tissue (negative) from well differentiated adipose lesions
Positive HMGA2 staining found in the following lesions
- 86% of conventional and intramuscular lipomas
- 67% of dedifferentiated liposarcomas
- 66.7% of papillary renal cell carcinomas (Cancer Med 2023;12:14851)
- 83.3% of atypical teratoid / rhabdoid tumors (Clin Cancer Res 2014;20:1179)
- 90% of esophageal squamous carcinomas (predominantly nuclear but may have some cytoplasmic staining) (Oncotarget 2016;7:25872)
- 98.1% of pancreatic ductal carcinomas (strong nuclear staining, some cytoplasmic) (J Cancer Res Clin Oncol 2021;147:3313)

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

Protein is encoded by HMGA2 gene located at chromosomal band 12q14-15 (Int J Mol Sci 2020;21:3151)
HMGA2 gene may be involved in various rearrangements involving 12q15
- Salivary gland neoplasms associated with recurrent translocations (Histopathology 2017;71:511)
- Deregulation in mesenchymal tumors (such as lipomas) often due to rearrangement of HMGA2 locus in 12q15 (Mol Cancer 2009;8:36)
Pleomorphic adenomas are associated with rearrangement of HMGA2 locus (Histopathology 2017;71:511)
Patients with pathogenic variants in HMGA2 have been reported in Silver-Russell syndrome (J Clin Endocrinol Metab 2020;105:dgaa273)

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?

HMGA2 enhances the proliferation of cancer cells by inhibiting the cell cycle and promoting apoptosis
HMGA2 is downregulated in many human malignancies
HMGA2 is primarily expressed in adult tissues and is absent in fetal tissues
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?

Beckwith-Wiedemann syndrome
Laron syndrome
Silver-Russell syndrome
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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