Research ArticleArticles
Open Access

Fusion of High Mobility Group AT-hook 2 Gene (HMGA2) With the Chromosome 12 Open Reading Frame 42 Gene (C12orf42) in an Aggressive Angiomyxoma With del(12)(q14q23) as the Sole Cytogenetic Anomaly

IOANNIS PANAGOPOULOS, LUDMILA GORUNOVA, KRISTIN ANDERSEN, INGVILD LOBMAIER, FRANCESCA MICCI and SVERRE HEIM
Cancer Genomics & Proteomics September 2022, 19 (5) 576-583; DOI: https://doi.org/10.21873/cgp.20342

Abstract

Background/Aim: Aggressive angiomyxomas are mostly found in the pelvic and perineal region and are prone to recur after surgery. Cytogenetic information is available on only nine such tumors. Herein, we report the cytogenetic anomaly and its molecular consequence in another aggressive angiomyxoma. Materials and Methods: An aggressive angiomyxoma found in a 33-year-old woman was examined using cytogenetic, RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), and Sanger sequencing techniques. Results: The karyotype of short-term cultured tumor cells was 46,XX,del(12) (q14q23)[9]/46,XX[2]. RNA sequencing detected fusion of the high mobility group AT-hook 2 gene (HMGA2) with the chromosome 12 open reading frame 42 gene (C12orf42). RT-PCR together with Sanger sequencing verified the presence of an HMGA2::C12orf42 fusion transcript. Conclusion: The present case carrying del(12)(q14q23) and an HMGA2::C12orf42 chimeric transcript strengthens the notion that involvement of HMGA2 and its misexpression are pathogenetically important in the development of aggressive angiomyxomas.

Key Words:

Aggressive angiomyxoma was first described by Steeper and Rosai as a distinctive, infiltrating soft-tissue tumor of the pelvis and perineum in nine female patients (1). The authors used the term “aggressive angiomyxoma” to emphasize the infiltrative nature of the neoplastic blood vessels and the fact that the tumor often recurs after surgery (1). Although aggressive angiomyxoma most often arises in the vulvovaginal region, perineum, and pelvis of reproductive age women (1-9), it has also been described in the scrotum, spermatic cord, and perineum of men (10-14). The larynx, oral floor, lung, supraclavicular fossa, and liver have also very occasionally been the sites of aggressive angiomyxomas (15-21). The tumors are composed of spindle cells that are immunohistochemically positive for desmin and vimentin. Numerous thick-walled blood vessels are embedded in an abundant myxoid matrix (9, 22). Over the years, cytogenetic information has been reported on only nine such tumors, all of them of vulvovaginal origin (Table I) (2, 3, 5-7, 23-27).

View this table:
Table I.

Genetically examined aggressive angiomyxomas, published and present case.

Herein, we report an aggressive angiomyxoma carrying a del(12)(q14q23) as the sole cytogenetic anomaly, resulting in fusion of the high mobility group AT-hook 2 (HMGA2) gene from 12q14 with the chromosome 12 open reading frame 42 (C12orf42) gene from 12q23.

Materials and Methods

Ethics Statement. The study was approved by the regional ethics committee (Regional komité for medisinsk forskningsetikk Sør-Øst, Norge, http://helseforskning.etikkom.no). Written informed consent was obtained from the patient to publication of the case details. The ethics committee’s approval included a review of the consent procedure. All patient information has been de-identified.

Tumor description. The surgical specimen was from the perineum of a 33-year-old woman. Microscopically, the tumor had characteristic spindled to stellate cells scattered in a myxoid and collagenous matrix with differently sized vessels spread throughout the lesion (Figure 1A). There was no atypia or necrosis. The scattered cells showed strong cytoplasmic immunohistochemical positivity for desmin (Figure 1B). Smooth muscle actin (SMA) positivity was seen in nodules close to some of the vessels (Figure 1C). Nuclear positivity for estrogen receptor (ER) and progesterone receptor (PGR) was seen in all cells (Figure 1D and E). The diagnosis was aggressive angiomyxoma.

Figure 1.
Figure 1.

Microscopic examination of the aggressive angiomyxoma. (A) Hematoxylin and eosin (HE)-stained section showing characteristic spindled to stellate cells scattered in a myxoid and collagenous matrix as well as differently sized vessels throughout the lesion, ×10. (B) Scattered cells showing strong cytoplasmic staining with desmin, ×10. (C) SMA positivity was seen in nodules close to some of the vessels, ×10. (D) Estrogen receptor (ER) nuclear positivity in all cells, ×10. (E) Progesterone receptor (PR) nuclear positivity in all cells, ×10.

G-banding and karyotyping. Part of the resected tumor was received for cytogenetic analysis according to our diagnostic routine. The tumor specimen was minced with scalpels into 1-2 mm fragments and then enzymatically disaggregated with collagenase II (Worthington, Freehold, NJ, USA). The resulting cells were cultured, harvested, and processed for cytogenetic examination using standard techniques (28). Chromosome preparations were G-banded with Wright’s stain (Sigma-Aldrich, St Louis, MO, USA) and examined (28). Metaphases were analyzed and karyograms prepared using the CytoVision computer-assisted karyotyping system (Leica Biosystems, Newcastle upon Tyne, UK). The karyotypes were described according to the International System for Human Cytogenomic Nomenclature (29).

RNA sequencing. Total RNA was extracted from a frozen (−80°C) part of the tumor specimen, adjacent to that used for cytogenetic analysis and histologic examination, using miRNeasy Mini Kit (Qiagen, Hilden, Germany). One μg of total RNA was sent to the Genomics Core Facility at the Norwegian Radium Hospital, Oslo University Hospital for high-throughput paired-end RNA-sequencing and 185×106 101-bp-length-reads were obtained. FASTQC software was used for quality control of the raw sequence data (available online at: http://www.bioinformatics.babraham.ac.uk/projects/fastqc/). The software FusionCatcher was used for the detection of possible HMGA2 fusion transcripts (30, 31).

Reverse transcription (RT) PCR and Sanger sequencing analyses. In order to confirm the existence of HMGA2 fusion (see below), RT-PCR and Sanger sequencing analyses were performed. cDNA was synthesized from one μg of total RNA in a 20 μl reaction volume using iScript Advanced cDNA Synthesis Kit for RT-qPCR according to the manufacturer’s instructions (Bio-Rad, Hercules, CA, USA). Then, cDNA corresponding to 20 ng of total RNA was used as template in a 25 μl reaction volume PCR assay containing 12.5 μl Premix Ex Taq™ DNA Polymerase Hot Start Version (Takara Bio Europe/SAS, Saint-Germain-en-Laye, France) and 0.4 μM of each of the forward and reverse primers (Table II). The primer combination ABL1-91F1/ABL1-404R1 was used to amplify a 338 bp cDNA fragment from the ABL1 gene (ABL proto-oncogene 1, non-receptor tyrosine kinase) in order to check the quality of the cDNA synthesis. To detect the HMGA2::C12orf42 fusion transcript, the primer combinations HMGA2-929F1/C12orf42-1144R1 and HMGA2-929F1/C12orf42-1093R1 were used.

View this table:
Table II.

Primers used for reverse transcription (RT)PCR amplification.

A C-1000 Thermal cycler (Bio-Rad) was used for PCR amplifications. The cycling profile was 30 s at 94°C followed by 35 cycles of 7 s at 98°C, 30 s at 60°C, 30 s at 72°C, and a final extension step for 5 min at 72°C. Three μl of the PCR products were stained with GelRed (Biotium, Fremont, CA, USA), analyzed by electrophoresis through 1.0% agarose gel, and photographed. The remaining PCR products were purified using the MinElute PCR Purification Kit (Qiagen) and Sanger sequenced with the dideoxy procedure using the BigDye Direct Cycle Sequencing Kit in accordance with the company’s recommendations (ThermoFisher Scientific, Waltham, MA, USA). The primers used for sequencing were the forward HMGA2-929F1 containing M13 forward sequence at its 5′-end (M13-forward-HMGA2-929F1: TGTAAAACGACGGCCAGT-ACCGGTGAGCCC TCTCCTAAGAG) and the reverse C12orf42-1093R1 containing the M13 reverse primer sequence at its 5′-end (M13-reverse-C12orf42-1093R1: CAGGAAACAGCTATGACC-TTCCCTAGAGCTGTTGCA AAGTTGTT). Sequencing was run on the Applied Biosystems SeqStudio Genetic Analyzer system (ThermoFisher Scientific).

The Basic Local Alignment Search Tool (BLAST) was used to compare the sequences obtained by Sanger sequencing with the NCBI reference sequences NM_003483.4 of HMGA2 and NM_001386867.1 (transcript variant 6) and NR_170336.1 (transcript variant 15, non-coding RNA) of C12orf42 (32). The BLAST-like alignment tool (BLAT) and the human genome browser at UCSC were used to map the sequences on the Human GRCh37/hg19 assembly (33).

Results

The G-banding analysis detected an interstitial deletion, del(12)(q14q23), as the sole karyotypic aberration in 9 of 11 examined metaphases. Thus, the karyotype was 46,XX,del(12)(q14q23)[9]/46,XX[2] (Figure 2A).

Figure 2.
Figure 2.

Genetic analyses of the aggressive angiomyxoma. (A) Partial karyotype showing del(12)(q14q23) together with the normal chromosome 12. Arrow indicates breakpoints. (B) Gel electrophoresis of reverse transcription (RT) PCR amplification products: Lane 1, amplification of a 338 bp ABL1 cDNA fragment using the primers ABL1-91F1 and ABL1-404R1; lane 2, amplification of an HMGA2::C12orf42 cDNA fragment with the primers HMGA2-929F1/C12orf42-1144R1; lane 3, amplification of an HMGA2::C12orf42 cDNA fragment with the primers HMGA2-929F1/C12orf42-1093R1. (C) Partial sequence chromatogram of the cDNA HMGA2::C12orf42 fragment amplified with the primers HMGA2-929F1/C12orf42-1144R1 showing the junction position of HMGA2 and C12orf42 (vertical dotted line). Exon 3 of HMGA2 is based on reference sequence NM_003483.4 corresponding to transcript variant 1of HMGA2. Exon 7 of C12orf42 is based on reference sequence NM_001386867.1 corresponding to transcript variant 6 of C12orf42. (D) The putative 106 amino acid long HMGA2 peptide containing amino acid residues 1-94 of HMGA2 (accession number NP_003474.1) corresponding to exons 1-4 of the gene, and 12 amino acid residues from the sequence from C12orf42 (ETTRRCICLNKK). The three AT-hook domains of HMGA2 are shown with red bold letters.

Analysis of the fastq files of the RNA sequencing data with the FusionCatcher software detected an HMGA2::C12orf42 chimeric transcript in which exon 4 of HMGA2 (nt 1093 in reference sequence with accession number NM_003483.4) was fused with the last, non-coding exon 7 of the C12orf42 reference sequence with accession number NM_001386867.1, which is identical to exon 11 in the C12orf42 reference sequence NR_170336.1 (transcript variant 15, non-coding RNA).

RT-PCR with the primer combinations HMGA2-929F1/C12orf42-1144R1 and HMGA2-929F1/C12orf42-1093R1, as well as further Sanger sequencing of the cDNA amplified fragments, verified the above-mentioned HMGA2::C12orf42 chimeric transcript (Figure 2B and C). The transcript was predicted to code for a putative 106 amino acid long peptide containing amino acid residues 1-94 of HMGA2 protein (accession number NP_003474.1), corresponding to exons 1-4 of the gene, and 12 amino acid residues from the sequence from C12orf42 (ETTRRCICLNKK) (Figure 2D).

Discussion

Genetic studies of aggressive angiomyxomas are very few but overwhelmingly implicate the HMGA2 gene in tumorigenesis (2-5, 7, 25, 27, 34). Out of nine published tumors with cytogenetic information, six had rearrangements of chromosomal bands 12q13-15 (Table I) (2, 3, 5, 7, 24, 25, 27), one had monosomy 12 among other changes (23), the eighth tumor showed monosomy of the X chromosome as the sole karyotypic aberration (26), and the ninth carried a t(5;8)(p15;q22) as the sole chromosomal change (6). Structural rearrangements of chromosome bands 12q13-15 are often found in benign mesenchymal tumors including soft tissue chondromas, lipomas, pulmonary chondroid hamartomas, and uterine leiomyomas; their common molecular denominator is rearrangement and transcriptional activation of the HMGA2 gene in 12q14 (35, 36).

In three studies, metaphase and/or interphase fluorescence in situ hybridization (FISH) experiments on aggressive angiomyxomas with break-apart probes for HMGA2 were performed, showing abnormal hybridization patterns indicative of HMGA2 rearrangement (4, 5, 7). In the large interphase FISH study by Madeiros and coworkers (5), 14 out of 42 tumors (33%) showed HMGA2 rearrangement.

At the molecular level, Kazmierczak and coworkers (25) detected an HMGA2-fusion transcript in an aggressive angiomyxoma with the karyotype 46,XX,der(5)t(5;12)(q31;p11), der(12)inv(12)(p11q15)t(5;12)(q31;p11) (it is often impossible to distinguish bands 12q14 and 12q15 in G-banded preparations). The chimeric transcript contained the first three exons of HMGA2 followed by an intergenic sequence from 12p11. This would correspond to a truncated peptide containing the first 83 amino acid residues of HMGA2, encoding the AT-hook domains (exons 1-3 of HMGA2) that bind to the minor groove of adenine-thymine (AT) rich DNA, and 7 amino acid residues (NKQDSQE) from the BF510360 sequence (27).

In an aggressive angiomyxoma with t(1;12)(p32;q15), Madeiros and coworkers (5) found two chimeric transcripts in which exon 5 of HMGA2, 81 bp after the stop codon, was fused with sequences from chromosome sub-band 1p32.2 (GenBank accession numbers EU004592 and EU004592).

Recently, Lee and coworkers (34) reported a chimeric HMGA2 transcript in which the first three exons of HMGA2 were fused in frame with exons 2 to 7 of the Yes1 associated transcriptional regulator gene (YAP1) from 11q22, in an aggressive angiomyxoma. The putative HMGA2::YAP1 protein would contain, in addition to the three AT-hook domains of HMGA2, all functional domains of YAP1 except its proline N-terminal part which is encoded by exon 1 of that gene.

The aggressive angiomyxoma we describe had an interstitial deletion, del(12)(q14q23), as the sole karyotypic aberration. It resulted in an HMGA2::C12orf42 chimeric transcript in which exon 4 of HMGA2 was fused with the last, non-coding exon 7 of C12orf42. The transcription of HMGA2 is from centromere to telomere whereas the transcription of C12orf42 is from telomere to centromere. Thus, additional submicroscopic genomic rearrangements, perhaps an inversion, probably accompanied the interstitial del(12) enabling the generation of a HMGA2::C12orf42 chimera. Regardless, the HMGA2::C12orf42 transcript would code for a peptide containing amino acid residues 1-94 of HMGA2 protein (the AT-hook domains) and 12 amino acid residues from the sequence from C12orf42 (ETTRRCICLNKK) (Figure 2D).

In two other aggressive angiomyxomas, which carried chromosome translocations t(8;12)(p12;q15) and t(11;12)(q23;q15) as sole anomalies, FISH and molecular investigations showed that the breakpoints on chromosome 12 were outside HMGA2 so that the entire coding part of HMGA2 was expressed (2, 3). In the aggressive angiomyxoma with t(8;12)(p12;q15), FISH analysis placed the breakpoint telomeric to HMGA2. Immunohistochemistry showed that the HMGA2 protein was localized in spindle-shaped tumor cells (2). In another three studies in which HMGA2 expression of aggressive angiomyxomas was assessed by immunohistochemical techniques, the HMGA2 protein was found in 90% of the tumors in two studies (37, 38) but in 68% in the third one (39).

The data presented above demonstrate a variability in transcriptional activation of HMGA2 (breakpoints within or outside HMGA2, different fusion partners, truncated or full-length HMGA2 protein or chimeric HMGA2-YAP1 protein) (2, 3, 5, 7, 27, 34). This variability is comparable to what is found in other benign mesenchymal tumors showing involvement of HMGA2, among them lipomas, pulmonary chondroid hamartomas, soft tissue chondromas, and uterine leiomyomas (36, 40-48).

Disruption of the HMGA2 locus thus separates exons 1-3 that code for the three AT-hook domains, from the 3′-untranslated region of the gene (3′-UTR) which regulates HMGA2 transcription (49-53). The existence of translocation breakpoints outside of the HMGA2 locus (upstream or downstream) suggests that dysregulation of HMGA2 by a mechanism different from that targeting the gene’s 3′-UTR (2, 3, 43, 47, 48, 54, 55) may also be important.

It is important to note that evidence for the involvement of truncated forms of HMGA2 and abnormal expression of full length HMGA2 in tumorigenesis also stems from studies of cultured cells and murine models (56-62). Thus, expression of truncated human HMGA2 encoding the three AT hook domains or HMGA2-LPP fusion transcript coding for the three AT hook domains of HMGA2 and the LIM domains of the lipoma preferred partner gene (LPP) protein resulted in neoplastic transformation of mouse embryonic fibroblasts (NIH3T3 cells) (56). Expression of truncated human HMGA2 caused otherwise normal human myometrial cells to form leiomyoma-like lesions (62). In an in vitro system using porcine chondrocytes from the elbow joint, recombinant HMGA2 protein significantly increased the proliferative activity of chondrocytes in a dose-dependent manner. Application of a truncated HMGA2 peptide containing the first two AT-hook domains of HMGA2 showed a growth-promoting effect similar to that of the wild type HMGA2 protein (60, 61). In transgenic mice, expression of truncated HMGA2 or overexpression of full-length protein gave rise to lipomas (57), mixed growth hormone/prolactin cell pituitary adenomas (58) or other neoplasms such as fibroadenomas of the breast and salivary gland adenomas (59). Finally, HMGA2 was in knockout mice found to be a key regulator of myoblast proliferation and myogenesis (63). Hmga2 knockout mice had reduced myoblast proliferation and less muscle growth whereas overexpression of the gene promoted myoblast growth (63).

In summary, the present case with del(12)(q14q23) as the sole karyotypic change demonstrated generation of an HMGA2::C12orf42 chimeric transcript as the key pathogenetic event. It underscores the notion that involvement of HMGA2 and/or its misexpression is central to the development of aggressive angiomyxoma.

Acknowledgements

This work was supported by grants from Radiumhospitalets Legater.

Footnotes

  • Authors’ Contributions

    IP designed and supervised the research, performed molecular genetic experiments, bioinformatics analysis, and wrote the manuscript. LG performed cytogenetic analysis. KA performed cytogenetic analysis, molecular genetic experiments, and interpreted the data. IL performed the pathological examination. FM evaluated the data. SH assisted with experimental design and writing of the manuscript. All Authors read and approved of the final manuscript.

  • Conflicts of Interest

    The Authors declare that they have no potential conflicts of interest.

  • Received March 29, 2022.
  • Revision received May 3, 2022.
  • Accepted June 6, 2022.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Steeper TA and
    2. Rosai J
    : Aggressive angiomyxoma of the female pelvis and perineum. Report of nine cases of a distinctive type of gynecologic soft-tissue neoplasm. Am J Surg Pathol 7(5): 463–475, 1983. PMID: 6684403. DOI: 10.1097/00000478-198307000-00009
    OpenUrlCrossRefPubMed
  2. ↵
    1. Nucci MR,
    2. Weremowicz S,
    3. Neskey DM,
    4. Sornberger K,
    5. Tallini G,
    6. Morton CC and
    7. Quade BJ
    : Chromosomal translocation t(8;12) induces aberrant HMGIC expression in aggressive angiomyxoma of the vulva. Genes Chromosomes Cancer 32(2): 172–176, 2001. PMID: 11550285. DOI: 10.1002/gcc.1179
    OpenUrlCrossRefPubMed
  3. ↵
    1. Micci F,
    2. Panagopoulos I,
    3. Bjerkehagen B and
    4. Heim S
    : Deregulation of HMGA2 in an aggressive angiomyxoma with t(11;12)(q23;q15). Virchows Arch 448(6): 838–842, 2006. PMID: 16568309. DOI: 10.1007/s00428-006-0186-5
    OpenUrlCrossRefPubMed
  4. ↵
    1. Rabban JT,
    2. Dal Cin P and
    3. Oliva E
    : HMGA2 rearrangement in a case of vulvar aggressive angiomyxoma. Int J Gynecol Pathol 25(4): 403–407, 2006. PMID: 16990720. DOI: 10.1097/01.pgp.0000209572.54457.7b
    OpenUrlCrossRefPubMed
  5. ↵
    1. Medeiros F,
    2. Erickson-Johnson MR,
    3. Keeney GL,
    4. Clayton AC,
    5. Nascimento AG,
    6. Wang X and
    7. Oliveira AM
    : Frequency and characterization of HMGA2 and HMGA1 rearrangements in mesenchymal tumors of the lower genital tract. Genes Chromosomes Cancer 46(11): 981–990, 2007. PMID: 17654722. DOI: 10.1002/gcc.20483
    OpenUrlCrossRefPubMed
  6. ↵
    1. Tsuji T,
    2. Yoshinaga M,
    3. Inomoto Y,
    4. Taguchi S and
    5. Douchi T
    : Aggressive angiomyxoma of the vulva with a sole t(5;8)(p15;q22) chromosome change. Int J Gynecol Pathol 26(4): 494–496, 2007. PMID: 17885504. DOI: 10.1097/pgp.0b013e31802cbc05
    OpenUrlCrossRefPubMed
  7. ↵
    1. Rawlinson NJ,
    2. West WW,
    3. Nelson M and
    4. Bridge JA
    : Aggressive angiomyxoma with t(12;21) and HMGA2 rearrangement: report of a case and review of the literature. Cancer Genet Cytogenet 181(2): 119–124, 2008. PMID: 18295664. DOI: 10.1016/j.cancergencyto.2007.11.008
    OpenUrlCrossRefPubMed
    1. Bigby SM,
    2. Symmans PJ,
    3. Miller MV,
    4. Dray MS and
    5. Jones RW
    : Aggressive angiomyxoma [corrected] of the female genital tract and pelvis-clinicopathologic features with immunohistochemical analysis. Int J Gynecol Pathol 30(5): 505–513, 2011. PMID: 21804399. DOI: 10.1097/PGP.0b013e318211d56c
    OpenUrlCrossRefPubMed
  9. ↵
    1. Sutton BJ and
    2. Laudadio J
    : Aggressive angiomyxoma. Arch Pathol Lab Med 136(2): 217–221, 2012. PMID: 22288973. DOI: 10.5858/arpa.2011-0056-RS
    OpenUrlCrossRefPubMed
  10. ↵
    1. Tsang WY,
    2. Chan JK,
    3. Lee KC,
    4. Fisher C and
    5. Fletcher CD
    : Aggressive angiomyxoma. A report of four cases occurring in men. Am J Surg Pathol 16(11): 1059–1065, 1992. PMID: 1471726.
    OpenUrlPubMed
    1. Iezzoni JC,
    2. Fechner RE,
    3. Wong LS and
    4. Rosai J
    : Aggressive angiomyxoma in males. A report of four cases. Am J Clin Pathol 104(4): 391–396, 1995. PMID: 7572787. DOI: 10.1093/ajcp/104.4.391
    OpenUrlCrossRefPubMed
    1. Idrees MT,
    2. Hoch BL,
    3. Wang BY and
    4. Unger PD
    : Aggressive angiomyxoma of male genital region. Report of 4 cases with immunohistochemical evaluation including hormone receptor status. Ann Diagn Pathol 10(4): 197–204, 2006. PMID: 16844560. DOI: 10.1016/j.anndiagpath.2005.09.002
    OpenUrlCrossRefPubMed
    1. Neyaz A,
    2. Husain N,
    3. Anand N and
    4. Srivastava P
    : Rare paratesticular aggressive angiomyxoma with negative oestrogen and progesterone receptors in a male patient. BMJ Case Rep 2018: bcr2017222164, 2018. PMID: 29866663. DOI: 10.1136/bcr-2017-222164
    OpenUrlCrossRefPubMed
  14. ↵
    1. Kirkilessis G,
    2. Kakavia K,
    3. Bougiouklis D,
    4. Papadopoulos A,
    5. Lampropoulos C and
    6. Kirkilessis I
    : Aggressive angiomyxoma to 57-year old man. J Surg Case Rep 2020(9): rjaa313, 2020. PMID: 32973997. DOI: 10.1093/jscr/rjaa313
    OpenUrlCrossRefPubMed
  15. ↵
    1. Teixeira-De-Magalhães F and
    2. Pardal-De-Oliveira F
    : Angiomyxoma of larynx. Report of one case of a myxoid fibrohistiocytic lesion. Pathologica 87(5): 539–543, 1995. PMID: 8868184.
    OpenUrlPubMed
    1. Yamashita Y,
    2. Tokunaga O and
    3. Goto M
    : Aggressive angiomyxoma of the oral floor: report of a case. J Oral Maxillofac Surg 62(11): 1429–1431, 2004. PMID: 15510368. DOI: 10.1016/j.joms.2004.02.015
    OpenUrlCrossRefPubMed
    1. Choi YD,
    2. Kim JH,
    3. Nam JH,
    4. Choi C,
    5. Na KJ and
    6. Song SY
    : Aggressive angiomyxoma of the lung. J Clin Pathol 61(8): 962–964, 2008. PMID: 18663059. DOI: 10.1136/jcp.2008.056788
    OpenUrlAbstract/FREE Full Text
    1. Pai CY,
    2. Nieh S,
    3. Lee JC,
    4. Lo CP and
    5. Lee HS
    : Aggressive angiomyxoma of supraclavicular fossa: a case report. Head Neck 30(6): 821–824, 2008. PMID: 18213718. DOI: 10.1002/hed.20747
    OpenUrlCrossRefPubMed
    1. Sylvester DC,
    2. Kortequee S,
    3. Moor JW,
    4. Woodhead CJ and
    5. Maclennan KA
    : Aggressive angiomyxoma of larynx: case report and literature review. J Laryngol Otol 124(7): 793–795, 2010. PMID: 19958565. DOI: 10.1017/S0022215109992350
    OpenUrlCrossRefPubMed
    1. Qi S,
    2. Li B,
    3. Peng J,
    4. Wang P,
    5. Li W,
    6. Chen Y,
    7. Cui X,
    8. Liu C and
    9. Li F
    : Aggressive angiomyxoma of the liver: a case report. Int J Clin Exp Med 8(9): 15862–15865, 2015. PMID: 26629089.
    OpenUrlPubMed
  21. ↵
    1. Sato K,
    2. Ohira M,
    3. Shimizu S,
    4. Kuroda S,
    5. Ide K,
    6. Ishiyama K,
    7. Kobayashi T,
    8. Tahara H,
    9. Shiroma N,
    10. Arihiro K,
    11. Imamura M,
    12. Chayama K and
    13. Ohdan H
    : Aggressive angiomyxoma of the liver: a case report and literature review. Surg Case Rep 3(1): 92, 2017. PMID: 28831707. DOI: 10.1186/s40792-017-0365-4
    OpenUrlCrossRefPubMed
  22. ↵
    1. Fetsch JF,
    2. Laskin WB,
    3. Lefkowitz M,
    4. Kindblom LG and
    5. Meis-Kindblom JM
    : Aggressive angiomyxoma: a clinicopathologic study of 29 female patients. Cancer 78(1): 79–90, 1996. PMID: 8646730. DOI: 10.1002/(SICI)1097-0142(19960701)78:1<79::AID-CNCR13>3.0.CO;2-4
    OpenUrlCrossRefPubMed
  23. ↵
    1. Horsman D,
    2. Berean K,
    3. Salski C and
    4. Clement P
    : Aggressive angiomyxoma of the pelvis: Cytogenetic findings in a single case. Cancer Genetics and Cytogenetics 56(1): 130, 2019. DOI: 10.1016/0165-4608(91)90436-X
    OpenUrlCrossRef
  24. ↵
    1. Betz J,
    2. Meloni A,
    3. U’ren L,
    4. Moore G and
    5. Sandberg A
    : Cytogenetic findings in a case of angiomyxoma of the vaginal wall. Cancer Genetics and Cytogenetics 84(2): 157, 2019. DOI: 10.1016/0165-4608(96)85316-7
    OpenUrlCrossRef
  25. ↵
    1. Kazmierczak B,
    2. Wanschura S,
    3. Meyer-Bolte K,
    4. Caselitz J,
    5. Meister P,
    6. Bartnitzke S,
    7. Van de Ven W and
    8. Bullerdiek J
    : Cytogenic and molecular analysis of an aggressive angiomyxoma. Am J Pathol 147(3): 580–585, 1995. PMID: 7677171.
    OpenUrlPubMed
  26. ↵
    1. Kenny-Moynihan MB,
    2. Hagen J,
    3. Richman B,
    4. McIntosh DG and
    5. Bridge JA
    : Loss of an X chromosome in aggressive angiomyxoma of female soft parts: a case report. Cancer Genet Cytogenet 89(1): 61–64, 1996. PMID: 8689613. DOI: 10.1016/0165-4608(95)00350-9
    OpenUrlCrossRefPubMed
  27. ↵
    1. Kazmierczak B,
    2. Dal Cin P,
    3. Wanschura S,
    4. Bartnitzke S,
    5. Van den Berghe H and
    6. Bullerdiek J
    : Cloning and molecular characterization of part of a new gene fused to HMGIC in mesenchymal tumors. Am J Pathol 152(2): 431–435, 1998. PMID: 9466569.
    OpenUrlPubMed
  28. ↵
    1. Rooney DE
    1. Mandahl N
    : Methods in solid tumour cytogenetics. In: Human cytogenetics: malignancy and acquired abnormalities. Rooney DE (ed.). New York, Oxford University Press, pp. 165–203, 2001.
  29. ↵
    1. McGowan-Jordan J,
    2. Simons A and
    3. Schmid M
    : ISCN 2016: An International System for Human Cytogenomic Nomenclature. Basel, Karger, pp. 140, 2016.
  30. ↵
    1. Kangaspeska S,
    2. Hultsch S,
    3. Edgren H,
    4. Nicorici D,
    5. Murumägi A and
    6. Kallioniemi O
    : Reanalysis of RNA-sequencing data reveals several additional fusion genes with multiple isoforms. PLoS One 7(10): e48745, 2012. PMID: 23119097. DOI: 10.1371/journal.pone.0048745
    OpenUrlCrossRefPubMed
  31. ↵
    1. Nicorici D,
    2. Satalan H,
    3. Edgren H,
    4. Kangaspeska S,
    5. Murumagi A,
    6. Kallioniemi O,
    7. Virtanen S and
    8. Kikku O
    : FusionCatcher - a tool for finding somatic fusion genes in paired-end RNA-sequencing data. bioRxiv, 2014. DOI: 10.1101/011650
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Altschul SF,
    2. Gish W,
    3. Miller W,
    4. Myers EW and
    5. Lipman DJ
    : Basic local alignment search tool. J Mol Biol 215(3): 403–410, 1990. PMID: 2231712. DOI: 10.1016/S0022-2836(05)80360-2
    OpenUrlCrossRefPubMed
  33. ↵
    1. Kent WJ
    : BLAT—the BLAST-like alignment tool. Genome Res 12(4): 656–664, 2002. PMID: 11932250. DOI: 10.1101/gr.229202
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Lee MY,
    2. da Silva B,
    3. Ramirez DC and
    4. Maki RG
    : Novel HMGA2-YAP1 fusion gene in aggressive angiomyxoma. BMJ Case Rep 12(5): e227475, 2019. PMID: 31142482. DOI: 10.1136/bcr-2018-227475
    OpenUrlCrossRefPubMed
  35. ↵
    1. Heim S and
    2. Mitelman F
    : Cancer Cytogenetics: Chromosomal and molecular genetic abberations of tumor cells. Fourth Edition edn. Wiley-Blackwell, 2015.
  36. ↵
    1. Unachukwu U,
    2. Chada K and
    3. D’Armiento J
    : High mobility group AT-Hook 2 (HMGA2) oncogenicity in mesenchymal and epithelial neoplasia. Int J Mol Sci 21(9): 3151, 2020. PMID: 32365712. DOI: 10.3390/ijms21093151
    OpenUrlCrossRefPubMed
  37. ↵
    1. Dreux N,
    2. Marty M,
    3. Chibon F,
    4. Vélasco V,
    5. Hostein I,
    6. Ranchère-Vince D,
    7. Terrier P and
    8. Coindre JM
    : Value and limitation of immunohistochemical expression of HMGA2 in mesenchymal tumors: about a series of 1052 cases. Mod Pathol 23(12): 1657–1666, 2010. PMID: 20834238. DOI: 10.1038/modpathol.2010.174
    OpenUrlCrossRefPubMed
  38. ↵
    1. McCluggage WG,
    2. Connolly L and
    3. McBride HA
    : HMGA2 is a sensitive but not specific immunohistochemical marker of vulvovaginal aggressive angiomyxoma. Am J Surg Pathol 34(7): 1037–1042, 2010. PMID: 20551826. DOI: 10.1097/PAS.0b013e3181e32a11
    OpenUrlCrossRefPubMed
  39. ↵
    1. Harkness R and
    2. McCluggage WG
    : HMGA2 is a useful marker of vulvovaginal aggressive angiomyxoma but may be positive in other mesenchymal lesions at this site. Int J Gynecol Pathol 40(2): 185–189, 2021. PMID: 32897956. DOI: 10.1097/PGP.0000000000000689
    OpenUrlCrossRefPubMed
  40. ↵
    1. Bartuma H,
    2. Hallor KH,
    3. Panagopoulos I,
    4. Collin A,
    5. Rydholm A,
    6. Gustafson P,
    7. Bauer HC,
    8. Brosjö O,
    9. Domanski HA,
    10. Mandahl N and
    11. Mertens F
    : Assessment of the clinical and molecular impact of different cytogenetic subgroups in a series of 272 lipomas with abnormal karyotype. Genes Chromosomes Cancer 46(6): 594–606, 2007. PMID: 17370328. DOI: 10.1002/gcc.20445
    OpenUrlCrossRefPubMed
    1. Bartuma H,
    2. Panagopoulos I,
    3. Collin A,
    4. Trombetta D,
    5. Domanski HA,
    6. Mandahl N and
    7. Mertens F
    : Expression levels of HMGA2 in adipocytic tumors correlate with morphologic and cytogenetic subgroups. Mol Cancer 8: 36, 2009. PMID: 19508721. DOI: 10.1186/1476-4598-8-36
    OpenUrlCrossRefPubMed
    1. Kazmierczak B,
    2. Rosigkeit J,
    3. Wanschura S,
    4. Meyer-Bolte K,
    5. Van de Ven WJ,
    6. Kayser K,
    7. Krieghoff B,
    8. Kastendiek H,
    9. Bartnitzke S and
    10. Bullerdiek J
    : HMGI-C rearrangements as the molecular basis for the majority of pulmonary chondroid hamartomas: a survey of 30 tumors. Oncogene 12(3): 515–521, 1996. PMID: 8637707.
    OpenUrlPubMed
  43. ↵
    1. Kazmierczak B,
    2. Meyer-Bolte K,
    3. Tran KH,
    4. Wöckel W,
    5. Breightman I,
    6. Rosigkeit J,
    7. Bartnitzke S and
    8. Bullerdiek J
    : A high frequency of tumors with rearrangements of genes of the HMGI(Y) family in a series of 191 pulmonary chondroid hamartomas. Genes Chromosomes Cancer 26(2): 125–133, 1999. PMID: 10469450.
    OpenUrlCrossRefPubMed
    1. Rogalla P,
    2. Kazmierczak B,
    3. Meyer-Bolte K,
    4. Tran KH and
    5. Bullerdiek J
    : The t(3;12)(q27;q14-q15) with underlying HMGIC-LPP fusion is not determining an adipocytic phenotype. Genes Chromosomes Cancer 22(2): 100–104, 1998. PMID: 9598796. DOI: 10.1002/(sici)1098-2264(199806)22:2<100::aid-gcc3>3.0.co;2-0
    OpenUrlCrossRefPubMed
    1. Rogalla P,
    2. Lemke I,
    3. Kazmierczak B and
    4. Bullerdiek J
    : An identical HMGIC-LPP fusion transcript is consistently expressed in pulmonary chondroid hamartomas with t(3;12)(q27-28;q14-15). Genes Chromosomes Cancer 29(4): 363–366, 2000. PMID: 11066083.
    OpenUrlCrossRefPubMed
    1. Dahlén A,
    2. Mertens F,
    3. Rydholm A,
    4. Brosjö O,
    5. Wejde J,
    6. Mandahl N and
    7. Panagopoulos I
    : Fusion, disruption, and expression of HMGA2 in bone and soft tissue chondromas. Mod Pathol 16(11): 1132–1140, 2003. PMID: 14614053. DOI: 10.1097/01.MP.0000092954.42656.94
    OpenUrlCrossRefPubMed
  47. ↵
    1. Schoenberg Fejzo M,
    2. Ashar HR,
    3. Krauter KS,
    4. Powell WL,
    5. Rein MS,
    6. Weremowicz S,
    7. Yoon SJ,
    8. Kucherlapati RS,
    9. Chada K and
    10. Morton CC
    : Translocation breakpoints upstream of the HMGIC gene in uterine leiomyomata suggest dysregulation of this gene by a mechanism different from that in lipomas. Genes Chromosomes Cancer 17(1): 1–6, 1996. PMID: 8889500. DOI: 10.1002/(SICI)1098-2264(199609)17:1<1::AID-GCC1>3.0.CO;2-0
    OpenUrlCrossRefPubMed
  48. ↵
    1. Quade BJ,
    2. Weremowicz S,
    3. Neskey DM,
    4. Vanni R,
    5. Ladd C,
    6. Dal Cin P and
    7. Morton CC
    : Fusion transcripts involving HMGA2 are not a common molecular mechanism in uterine leiomyomata with rearrangements in 12q15. Cancer Res 63(6): 1351–1358, 2003. PMID: 12649198.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Borrmann L,
    2. Wilkening S and
    3. Bullerdiek J
    : The expression of HMGA genes is regulated by their 3′UTR. Oncogene 20(33): 4537–4541, 2001. PMID: 11494149. DOI: 10.1038/sj.onc.1204577
    OpenUrlCrossRefPubMed
    1. Lee YS and
    2. Dutta A
    : The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 21(9): 1025–1030, 2007. PMID: 17437991. DOI: 10.1101/gad.1540407
    OpenUrlAbstract/FREE Full Text
    1. Mayr C,
    2. Hemann MT and
    3. Bartel DP
    : Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315(5818): 1576–1579, 2007. PMID: 17322030. DOI: 10.1126/science.1137999
    OpenUrlAbstract/FREE Full Text
    1. Klemke M,
    2. Meyer A,
    3. Hashemi Nezhad M,
    4. Belge G,
    5. Bartnitzke S and
    6. Bullerdiek J
    : Loss of let-7 binding sites resulting from truncations of the 3′ untranslated region of HMGA2 mRNA in uterine leiomyomas. Cancer Genet Cytogenet 196(2): 119–123, 2010. PMID: 20082846. DOI: 10.1016/j.cancergencyto.2009.09.021
    OpenUrlCrossRefPubMed
  53. ↵
    1. Kristjánsdóttir K,
    2. Fogarty EA and
    3. Grimson A
    : Systematic analysis of the Hmga2 3′ UTR identifies many independent regulatory sequences and a novel interaction between distal sites. RNA 21(7): 1346–1360, 2015. PMID: 25999317. DOI: 10.1261/rna.051177.115
    OpenUrlAbstract/FREE Full Text
  54. ↵
    1. Merscher S,
    2. Marondel I,
    3. Pedeutour F,
    4. Gaudray P,
    5. Kucherlapati R and
    6. Turc-Carel C
    : Identification of new translocation breakpoints at 12q13 in lipomas. Genomics 46(1): 70–77, 1997. PMID: 9403060. DOI: 10.1006/geno.1997.4993
    OpenUrlCrossRefPubMed
  55. ↵
    1. Dal Cin P,
    2. Thomas A and
    3. Weremowicz S
    : An intragenic rearrangement of HMGA2 is not necessary for lipoma formation. Cancer Genet Cytogenet 149(2): 178–179, 2004. PMID: 15036898. DOI: 10.1016/j.cancergencyto.2003.07.005
    OpenUrlCrossRefPubMed
  56. ↵
    1. Fedele M,
    2. Berlingieri MT,
    3. Scala S,
    4. Chiariotti L,
    5. Viglietto G,
    6. Rippel V,
    7. Bullerdiek J,
    8. Santoro M and
    9. Fusco A
    : Truncated and chimeric HMGI-C genes induce neoplastic transformation of NIH3T3 murine fibroblasts. Oncogene 17(4): 413–418, 1998. PMID: 9696033. DOI: 10.1038/sj.onc.1201952
    OpenUrlCrossRefPubMed
  57. ↵
    1. Arlotta P,
    2. Tai AK,
    3. Manfioletti G,
    4. Clifford C,
    5. Jay G and
    6. Ono SJ
    : Transgenic mice expressing a truncated form of the high mobility group I-C protein develop adiposity and an abnormally high prevalence of lipomas. J Biol Chem 275(19): 14394–14400, 2000. PMID: 10747931. DOI: 10.1074/jbc.m000564200
    OpenUrlAbstract/FREE Full Text
  58. ↵
    1. Fedele M,
    2. Battista S,
    3. Kenyon L,
    4. Baldassarre G,
    5. Fidanza V,
    6. Klein-Szanto AJ,
    7. Parlow AF,
    8. Visone R,
    9. Pierantoni GM,
    10. Outwater E,
    11. Santoro M,
    12. Croce CM and
    13. Fusco A
    : Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas. Oncogene 21(20): 3190–3198, 2002. PMID: 12082634. DOI: 10.1038/sj.onc.1205428
    OpenUrlCrossRefPubMed
  59. ↵
    1. Zaidi MR,
    2. Okada Y and
    3. Chada KK
    : Misexpression of full-length HMGA2 induces benign mesenchymal tumors in mice. Cancer Res 66(15): 7453–7459, 2006. PMID: 16885341. DOI: 10.1158/0008-5472.CAN-06-0931
    OpenUrlAbstract/FREE Full Text
  60. ↵
    1. Richter A,
    2. Hauschild G,
    3. Murua Escobar H,
    4. Nolte I and
    5. Bullerdiek J
    : Application of high-mobility-group-A proteins increases the proliferative activity of chondrocytes in vitro. Tissue Eng Part A 15(3): 473–477, 2009. PMID: 18721076. DOI: 10.1089/ten.tea.2007.0308
    OpenUrlCrossRefPubMed
  61. ↵
    1. Richter A,
    2. Lübbing M,
    3. Frank HG,
    4. Nolte I,
    5. Bullerdiek JC and
    6. von Ahsen I
    : High-mobility group protein HMGA2-derived fragments stimulate the proliferation of chondrocytes and adipose tissue-derived stem cells. Eur Cell Mater 21: 355–363, 2011. PMID: 21484705. DOI: 10.22203/ecm.v021a26
    OpenUrlCrossRefPubMed
  62. ↵
    1. Mas A,
    2. Cervelló I,
    3. Fernández-Álvarez A,
    4. Faus A,
    5. Díaz A,
    6. Burgués O,
    7. Casado M and
    8. Simón C
    : Overexpression of the truncated form of High Mobility Group A proteins (HMGA2) in human myometrial cells induces leiomyoma-like tissue formation. Mol Hum Reprod 21(4): 330–338, 2015. PMID: 25542836. DOI: 10.1093/molehr/gau114
    OpenUrlCrossRefPubMed
  63. ↵
    1. Li Z,
    2. Gilbert JA,
    3. Zhang Y,
    4. Zhang M,
    5. Qiu Q,
    6. Ramanujan K,
    7. Shavlakadze T,
    8. Eash JK,
    9. Scaramozza A,
    10. Goddeeris MM,
    11. Kirsch DG,
    12. Campbell KP,
    13. Brack AS and
    14. Glass DJ
    : An HMGA2-IGF2BP2 axis regulates myoblast proliferation and myogenesis. Dev Cell 23(6): 1176–1188, 2012. PMID: 23177649. DOI: 10.1016/j.devcel.2012.10.019
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Fusion of High Mobility Group AT-hook 2 Gene (HMGA2) With the Chromosome 12 Open Reading Frame 42 Gene (C12orf42) in an Aggressive Angiomyxoma With del(12)(q14q23) as the Sole Cytogenetic Anomaly
IOANNIS PANAGOPOULOS, LUDMILA GORUNOVA, KRISTIN ANDERSEN, INGVILD LOBMAIER, FRANCESCA MICCI, SVERRE HEIM
Cancer Genomics & Proteomics Sep 2022, 19 (5) 576-583; DOI: 10.21873/cgp.20342
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords