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.
Pathology
truncated HMGA2 isoforms
12q14 (HMGA2) rearrangements in tumors
- pulmonary chondroid hamartoma
- lipoma (16133369)
- pleomorphic salivary adenoma (9484777)
- uterine leiomyoma
- vaginal leiomyoma (17654722)
- myelodyplasia
- benign mesenchymoma (chondrolipoangioma) (12021922)
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 by tumors
aggressive angiomyxoma of the lower genital tract (33%) (16990720, 17654722)
- t(8;12) (11550285)
- t(1;12)(p32;q15) (17654722)
- t(12;21)(q15;q21.1) (18295664)
pulmonary chondroid hamartoma (44.7%) (14621194)
- t(12;14)(q14;q24) (12699895)
- t(3;12)(q27;q14) (HMGA2/LPP fusion gene) (12505264, 16271958, 11890997)
HMGA2 fusion genes
HMGA2/NFIB fusion gene in
HMGA2/FHIT in a pleomorphic adenoma of the parotid gland (8988031, 18828159)
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)
HMGA2 amplification in 12q13-15 amplification (12q13-15 amplicon) with MDM2 (18214854)
pleomorphic adenoma of the parotid gland (18828159)
HMGA2 overexpression in tumors
uterine leiomyomas
salivary gland pleomorphic adenoma
lipomas
Miscelllaneous
HMGA2 protein expression correlates with lymph node metastasis and increased tumor grade in pancreatic ductal adenocarcinoma. (18843278)
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.
References
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