HMGA2 (high mobility group AT-hook 2)

Other names	HMGIC (High mobility group protein isoform I-C)
HGNC (Hugo)	HMGA2
LocusID (NCBI)	8091
Location	12q14.3
Location_base_pair	Starts at 66218240 and ends at 66360071 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order	telomeric to CDK4, centromeric to MDM2
	Probe(s) - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics

Description	5 exons, spans approximately 160 kb; a sixth alternative terminal exon within intron 3 has been described
Transcription	RNA: 4.1 kb. Transcription initiated from two different promoter regions. A polymorphic dinucleotide repeat upstream of the ATG start codon strongly regulates HMGA2 expression. Moreover, HMGA2 is controlled by negatively acting regulatory elements within the 3'UTR

Description	109 amino acids; three DNA binding domains (AT hooks) linked to the carboxy-terminal acidic domain that does not activate transcription
Expression	fetal tissues: expression in various tissues, prominent in kidney, liver and uterus; adult tissues: no expression except in lung and kidney; tumors: expression in benign mesenchymal tumor tissues correlated to 12q15 rearrangements; expressed in malignant tumours (e.g., in breast tumours, pancreas tumours, lung tumours, nerve system tumours, oral cavity tumours).
Localisation	nuclear
Function	architectural factor, non histone, preferential binding to AT rich sequences in the minor groove of DNA helix; the precise function remains to be elucidated; probable role in regulation of cell proliferation
Homology	member of the HMGI protein family

Entity	MESENCHYMAL BENIGN TUMORS as follows:
Entity	Lipoma
Disease	benign adipocyte tumor
Prognosis	good
Cytogenetics	various rearrangements involving 12q15 (translocations, inversions, deletions...); reciprocal translocations involve 12q15 with different partners such as chromosomes 1, 2, 3, 7, 10, 11, 13, 15, 17, 21, X; the most frequent anomaly is t(3;12)(q27-28;q15); cryptic rearrangements, such as paracentric inversions not detectable by conventional cytogenetics but detectable by FISH, have been described
Hybrid/Mutated Gene	for t(3;12): HMGIC-LPP (LPP: lipoma preferred partner; 3q27-28); a gene located in 13q, LHFP (lipoma HMGIC fusion partner) was found to be fused with HMGIC in one case of lipoma; one lipoma displayed fusion of HMGA2 exon 4 with a sequence from intron 4, indicating abnormal splicing; HMGA2-CMKOR1 in three cases with aberrations involving 2q35-37 and 12q13-15; HMGA2-NFIB in one lipoma;
Abnormal Protein	HMGIC-LPP; the three AT hook domains at the aminoterminal of HMGIC are fused to the LIM domain of LPP; another fusion protein due to the fusion of HMGIC with a putative gene located at 15q24 predicted to encode a protein with a serine/threonine-rich domain has also been described
Oncogenesis	the relevance of the exact role LPP in the HMGA2-LPP fusion is not established yet, but the transactivation functions of the LPP LIM domains is retained in the fusion protein and the fusion protein can function as a transcription factor; the truncation of HMGA2 by itself may have a role in the tumorigenesis
Entity	Uterine leiomyoma (uterine fibroids)
Disease	benign mesenchymal tumors
Prognosis	good
Cytogenetics	approximately 40% of uterine leiomyomas have structural chromosomal rearrangements, about 10% of which involve 12q15 (translocations, inversions, deletions...); the most frequent anomaly is t(12;14)(q15;q23-24)
Hybrid/Mutated Gene	in a majority of cases, there is no fusion gene: the breakpoint is located 10 kb up to 100 kb 5' to HMGIC; the recombinational repair gene RAD51B is a candidate to be the partner gene of HMGIC in t(12;14). In two cases (out of 81 primary tumors) exon 7 of RAD51B was fused in frame to either exon 2 or 3 of the HMGA2 gene; in one case with paracentric inversion, HMGIC exon 3 was fused to ALDH2 exon 13 (12q24.1); in one case (no cytogenetic analysis) HMGIC exon 3 was fused to COX6C 3' UTR (8q22-23); in one case, with apparently normal karyotype, exon 3 of HMGIC was fused to retrotransposon-like sequences RTVLH 3' LTRs; three fusion transcripts contained 3' cryptic exonic sequences present in intron 3 of the HMGA2 gene (breakpoints downstream of exons 3 or 4), suggesting that they are due to alternative splicing; one case displayed fusion of the first two exons of HMGA2 to the 3' portion of the CCNB1IP1/C14orf18/HEI10 gene
Abnormal Protein	HMGIC-ALDH2: ALDH2 contribution was only 10 amino acids;
Oncogenesis	HMGIC-ALDH2: it is suggested that the truncation of HMGIC, rather than fusion may be responsible for tumorigenesis; the 3' untranslated region may stabilize the HMGIC messenger RNA
Entity	Pleomorphic adenoma of the salivary gland (or mixed salivary gland tumor)
Disease	benign tumors from the major or minor salivary glands
Prognosis	good
Cytogenetics	approximately 12% of pleomorphic adenomas of salivary glands show abnormalities involving HMGIC in 12q15; the most frequent aberration is t(9;12)(p24.1;q15)
Hybrid/Mutated Gene	in t(9;12): HMGIC-NFIB fusion; another type of fusion HMGIC-FHIT (3p14.2) has also been described
Entity	Pulmonary chondroid hamartoma of the lung
Disease	benign mesenchymal tumors of the lung
Prognosis	good
Cytogenetics	various rearrangements involving 12q15 leading to HMGIC dysregulation; cryptic rearrangements such as paracentric inversions not detectable by conventional cytogenetics but detectable by FISH have been described
Hybrid/Mutated Gene	in two cases with apparently normal karyotypes, exon 3 of HMGIC was fused to retrotransposon-like sequences RTVLH 3' LTRs; in cases with t(3;12)(q27-28;q14-15) (see lipomas), a fusion of HMGA2-LPP was described; only 1/61 cases with normal karyotype displayed HMGA2-LPP fusion; three cases with rearrangements involving 12q14-15 and 13q12-14 lacked rearrangements of HMGA2-LHFP;
Entity	Endometrial polyps
Disease	uterine benign tumors
Prognosis	good
Cytogenetics	various rearrangements involving 12q15 leading to HMGIC dysregulation; cryptic rearrangements such as paracentric inversions not detectable by conventional cytogenetics but detectable by FISH have been described; in one case, HMGIC was amplified and overexpressed
Entity	Myofibroblastic inflammatory tumor
Disease	benign mesenchymal tumors
Prognosis	good
Cytogenetics	in one case, a complex rearrangement involving chromosomes 12 (in 12q15), 4 and 21 was described
Hybrid/Mutated Gene	an aberrant transcript was produced by the fusion of HMGIC exon 3 to an ectopic sequence originating from the third intron of HMGIC
Entity	Chondrolipoangioma
Disease	a rare benign type of mesenchyomas composed predominantly of cartilage and adipose tissue with vascular elements and myxoid elements
Cytogenetics	One case demonstrated t(12;15)(q13;q26). FISH analysis revealed rearrangement of chromosomes 2, 12 and 15 and HMGA2.
Entity	Chondromas
Disease	benign cartilage tumours
Cytogenetics	HMGA2 was expressed in 4/6 soft tissue chondromas (all with 12q-rearrangements cytogenetically), three cases showed truncated (exons 1-3) transcripts, one case displayed a t(3;12)(q27;q15) and RT-PCR demonstrated a HMGA2-LPP fusion transcript composed of HMGA2 exons 1-3 and LPP exons 9-11.
Entity	Hyaline vascular Castleman's disease
Cytogenetics	one case with der(6)t(6;12)(q23;q15)del(12)(q15) is described.
Hybrid/Mutated Gene	a combined immunologic-cytogenetic approach demonstrated HMGA2 rearrangement in follicular dendritic cells
Entity	Prolactinoma
Disease	prolactin-secreting pituary adenoma, non-metastasizing
Cytogenetics	trisomy 12 nonrandom finding in pituary adenomas
Hybrid/Mutated Gene	HMGA2 locus amplified in 7/8 prolactinomas
Entity	Aggressive angiomyxoma of the vulva
Disease	myxoid mesenchymal neoplasm
Prognosis	infiltrative neoplasm, locally destructive recurrences, no metastatic potential
Cytogenetics	one case displayed t(8;12)(p12;q15)
Hybrid/Mutated Gene	FISH demonstrated a breakpoint 3' of the gene, the tumour expressed HMGA2
Entity	MALIGNANT TUMORS as follows:
Entity	Well-differentiated liposarcoma
Disease	malignant adipocyte tumor; peripheral or retroperitoneal location
Prognosis	rather good; borderline malignancy; locally aggressive, rarely metastasizes
Cytogenetics	supernumerary ring or giant marker chromosomes containing 12q14-15 amplification (surrounding MDM2); HMGIC is frequently amplified together with MDM2; rearrangement of HMGA2, in addition to amplification has been described
Hybrid/Mutated Gene	ectopic sequences from 12q14-15, 1q24, 11q14, and chromosome 2 was shown to be fused to HMGA2 exon 2 or 3
Entity	Uterine leiomyosarcoma
Disease	malignant counterpart of uterine leiomyoma
Prognosis	poor
Cytogenetics	12q13-15 region is recurrently amplified
Hybrid/Mutated Gene	HMGA2 amplified within this region
Entity	Osteosarcoma
Disease	malignant tumor
Hybrid/Mutated Gene	in one osteosarcoma cell line (OsA-Cl) the three DNA binding domains of HMGIC fused to the keratan sulfate protein glycan gene LUM (12q22-23); LUM was fused out of frame, and only 3 amino acids were fused to HMGIC; in addition, the rearranged gene was amplified
Entity	with myeloid metaplasia
Disease	rare chronic myeloproliferative disorder
Prognosis	variable
Cytogenetics	one case with t(4;12)(q32;q15) and one case with t(5;12)(p14;q15)
Hybrid/Mutated Gene	FISH analysis suggested breakpoint in HMGA2, RT-PCR revealed that HMGA2 is expressed in blood mononuclear cells from patients with this disease
Entity	Acute lymphoblastic leukaemia
Disease	Heterogenous disease that arises in precursor B or T cells
Cytogenetics	One case with a t(9;12)(p22;q14), frequent deletions at 12q14.3
Hybrid/Mutated Gene	t(9;12): FISH analysis indicated a breakpoint in the 5' region of the gene, RT-PCR showed overexpression of HMGA2 lacking the carboxyterminal tail; deletions covering the 5' end of HMGA2

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