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HMGA2

MIM.600698 12q14-q15 HGNC:5009 Entrez:8091

Wednesday 27 October 2004

Definition: The high mobility group A2 (HMGA2) protein is an architectural transcription factor that has recently been implicated in the development and progression of malignant tumors.

Function

HMGA2 gene encodes a protein that belongs to the non-histone chromosomal high mobility group (HMG) protein family (HMGs). HMG proteins (HMGs) function as architectural factors and are essential components of the enhancesome. This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor.

A gene knock out study of the mouse counterpart demonstrated that this gene is involved in diet-induced obesity.

Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Pathology

- truncated HMGA2 isoforms

- 12q14 (HMGA2) rearrangements in tumors

- bisruption and aberrant expression of HMGA2 by chromosomal translocations in myeloid malignancies (15618963)

  • myelodyplasia

- constitutional rearrangement of HMGA2 in a phenotype including extreme somatic overgrowth, advanced endochondral bone and dental ages, a cerebellar tumor, and multiple lipomas (15593017)

- 12q14 (HMGA2) rearrangements in tumors

- HMGA2 fusion genes

  • HMGA2/RDC1 fusion protein expression in lipomas as the result of chromosome aberrations involving 2q35-37 and 12q13-15. (Fusion of RDC1 with HMGA2 in lipomas)

- pleomorphic adenoma of the parotid gland (18828159)

HMGA2 overexpression in tumors

- uterine leiomyomas
- salivary gland pleomorphic adenoma
- lipomas

Immunochemistry

- HMGA2 is a sensitive but not specific immunohistochemical marker of vulvovaginal aggressive angiomyxoma. (20551826)

Miscelllaneous

- HMGA2 protein expression correlates with lymph node metastasis and increased tumor grade in pancreatic ductal adenocarcinoma. (18843278)

miRNAs

HMGA2 was identified as one of target genes of the let-7 family of miRNAs and has been found to be suppressed by let-7 in vitro. (17243163)

Physiopathology

Rearrangement and overexpression of HMGA2 are observed in lipomas and in other benign tumors such as uterine leiomyomas and salivary gland pleomorphic adenomas.

In lipomas, the preferential clustering of HMGA2 breakpoints in the third intron results in the replacement of the acidic C-terminal domain by a variety of ectopic sequences. In addition, extragenic breakpoints located 5 or 3 to HMGA2 similar to the rearrangements observed in uterine leiomyomas also occur in lipomas.

Some reports based on small series have shown the amplification and overexpression of HMGA2 in a subset of WDLPS/DDLPS.

Pedeutour et al. have demonstrated the amplification of exons 1-2 of HMGA2 in all the 38 WDLPS/DDLPS cases studied, against the nonconsistent amplification of exons 3-5.

Some authors have proposed that the truncation of HMGA2 followed or not by the addition of ectopic sequences might be the critical steps in HMGA2 oncogenicity.

Moreover, some tumors with 12q rearrangements retain the full coding region of HMGA2, suggesting a nondependence of the HMGA2 oncogenic potential on the nature of the transcript.

In adipose tissue tumors, the dysregulation of HMGA2 may be sufficient to lead to only benign lesions. In contrast, the dysregulation of HMGA2 might cause a malignant phenotype when coupled with MDM2 amplification, as suggested by a study showing that the expression of MDM2 or CDK4 allowed human diploid fibroblast to by-pass HMGA2-induced proliferation arrest.

Some results identifying variability in the dysregulation pattern of HMGA2 in WDLPS/DDLPS, strongly suggest that a misexpression of HMGA2, whatever the mechanism, might be sufficient for tumorigenesis.

Although CDK4 certainly plays an important role in a majority of cases, our results favor MDM2-HMGA2 instead of MDM2-CDK4 as the crucial couple of genes in WDLPS/DDLPS pathogenesis. However, cooperation between HMGA2 and CDK4, when amplified, may also play an important role.

Transgenic mice

Zaidi et al. reported no difference in the phenotype of benign tumors developed in transgenic mice expressing either a full-length or a truncated HMGA2 transcript under the control of a differentiated adipocyte-specific promoter.

The observation that the tumors developed in HMGA2 transgenic mice were always benign raises the question of the role of HMGA2 in malignancy.

let-7 microRNA

In addition, HMGA2 overexpression could also result from the disruption of the 3UTR causing the loss of function of let-7, a microRNA specifically involved in the posttranscriptional repression of HMGA2.

Diagnostic use

- Diagnostic value of HMGAs in discriminating adenocarcinoma from adenoma or reactive atypia in ampulla and common bile duct biopsies. (23530587)

  • Expression of HMGA1 is seen in 21% of the reactive atypia cases, 42% of adenomas, and 91% of adenocarcinomas.
  • HMGA2 is positive in 14% of reactive atypias, 42% of adenomas, and 86% of adenocarcinomas.
  • The staining intensity of HMGA1 and HMGA2 is also significantly higher in adenocarcinomas than in adenomas or reactive atypias.
  • Coexpression of HMGA1 and HMGA2 is found in 86% of adenocarcinomas, 0% of reactive atypias, and 8% of adenomas.
  • p53 and β-catenin expression seems not to provide additional value for discriminating adenocarcinoma from reactive atypia or adenoma.
  • HMGA1 and HMGA2 might serve to discriminate between reactive atypia, adenoma and adenocarcinoma in ampulla and common bile duct biopsies.

References

- Diagnostic value of HMGAs, p53 and β-catenin in discriminating adenocarcinoma from adenoma or reactive atypia in ampulla and common bile duct biopsies. Zakharov V, Ren B, Ryan C, Cao W. Histopathology. 2013 Apr;62(5):778-87. doi : 10.1111/his.12084 PMID: 23530587

- HMGA2 expression analysis in cytological and paraffin-embedded tissue specimens of thyroid tumors by relative quantitative RT-PCR. Jin L, Lloyd RV, Nassar A, Lappinga PJ, Sebo TJ, Swartz K, Seys AR, Erickson-Johnson MR, Roth CW, Evers BR, Oliveira AM, Zhang J. Diagn Mol Pathol. 2011 Jun;20(2):71-80. PMID: 21532495

- HMGA2 is a sensitive but not specific immunohistochemical marker of vulvovaginal aggressive angiomyxoma. McCluggage WG, Connolly L, McBride HA. Am J Surg Pathol. 2010 Jul;34(7):1037-42. PMID: 20551826

- HMGA2: A Potential Biomarker Complement to P53 for Detection of Early-stage High-grade Papillary Serous Carcinoma in Fallopian Tubes. Wei JJ, Wu J, Luan C, Yeldandi A, Lee P, Keh P, Liu J. Am J Surg Pathol. 2009 Oct 28. PMID: 19898227

- Hristov AC, Cope L, Reyes MD, Singh M, Iacobuzio-Donahue C, Maitra A, Resar LM. HMGA2 protein expression correlates with lymph node metastasis and increased tumor grade in pancreatic ductal adenocarcinoma. Mod Pathol. 2008 Aug 29. PMID: 18843278

- Persson F, Andrén Y, Winnes M, Wedell B, Nordkvist A, Gudnadottir G, Dahlenfors R, Sjögren H, Mark J, Stenman G. High-resolution genomic profiling of adenomas and carcinomas of the salivary glands reveals amplification, rearrangement, and fusion of HMGA2. Genes Chromosomes Cancer. 2008 Sep 30. PMID: 18828159

- Italiano A, Bianchini L, Keslair F, Bonnafous S, Cardot-Leccia N, Coindre JM, Dumollard JM, Hofman P, Leroux A, Mainguené C, Peyrottes I, Ranchere-Vince D, Terrier P, Tran A, Gual P, Pedeutour F. HMGA2 is the partner of MDM2 in well-differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon. Int J Cancer. 2008 Jan 23; PMID: 18214854

- Rabban JT, Dal Cin P, Oliva E. HMGA2 rearrangement in a case of vulvar aggressive angiomyxoma. Int J Gynecol Pathol. 2006 Oct;25(4):403-7. PMID: 16990720

- Dal Cin P, Thomas A, Weremowicz S. An intragenic rearrangement of HMGA2 is not necessary for lipoma formation. Cancer Genet Cytogenet. 2004 Mar;149(2):178-9. PMID: 15036898

- Dahlen A, Mertens F, Rydholm A, Brosjo O, Wejde J, Mandahl N, Panagopoulos I. Fusion, disruption, and expression of HMGA2 in bone and soft tissue chondromas. Mod Pathol. 2003 Nov;16(11):1132-40. PMID: 14614053

- Pentimalli F, Dentice M, Fedele M, Pierantoni GM, Cito L, Pallante P, Santoro M, Viglietto G, Dal Cin P, Fusco A. Suppression of HMGA2 protein synthesis could be a tool for the therapy of well differentiated liposarcomas overexpressing HMGA2. Cancer Res. 2003 Nov 1;63(21):7423-7. PMID: 14612541

- Quade BJ, Weremowicz S, Neskey DM, Vanni R, Ladd C, Dal Cin P, Morton CC. Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15. Cancer Res. 2003 Mar 15;63(6):1351-8. PMID: 12649198

- Van Dorpe J, Dal Cin P, Weremowicz S, Van Leuven F, de Wever I, Van den Berghe H, Fletcher CD, Sciot R. Translocation of the HMGI-C ( HMGA2) gene in a benign mesenchymoma (chondrolipoangioma). Virchows Arch. 2002 May;440(5):485-90. PMID: 12021922

- Berner JM, Meza-Zepeda LA, Kools PF, Forus A, Schoenmakers EF, Van de Ven WJ, Fodstad O, Myklebost O. HMGIC, the gene for an architectural transcription factor, is amplified and rearranged in a subset of human sarcomas. Oncogene. 1997 Jun 19;14(24):2935-41. PMID: 9205100

- Kazmierczak B, Dal Cin P, Sciot R, Van den Berghe H, Bullerdiek J. Inflammatory myofibroblastic tumor with HMGIC rearrangement. Cancer Genet Cytogenet. 1999 Jul 15;112(2):156-60. PMID: 10686944