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Partial karyotypes of cases 1 and 2. (A) In case 1, the der(4) t(4;12) (q27~28; q14~15) and der(12) t(4;12), together with the corresponding normal chromosome homologs, are shown. (B) In case 2, the der(1), der(4) and der(12) are shown, together with the corresponding normal chromosome homologs from the t(1;4;12)(q21;q27~28;q14~15). Breakpoint positions are indicated by arrows. der, derivative chromosome
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Lipomas are common benign soft tissue tumors whose genetic and cytogenetic features are well characterized. The karyotype is usually near- or pseudodiploid with characteristic structural chromosomal aberrations. The most common rearrangements target the high mobility group AT-hook 2 (HMGA2) gene in 12q14.3, with breakpoints occur- ring within or ou...
Context in source publication
Context 1
... and HMGA2 fusions of the examined lipomatous tumors. In all 6 cases (3 males and 3 females), there was recombination between the chromosome bands 12q14~15 and 4q27~28. In total, 5 cases carried t(4;12)(q14~15;q27~28) as the sole karyotypic aberration, whereas 1 lipoma (case 2) had a three-way translocation t(1;4;12)(q21;q27~28;q14~15) ( Fig. ...
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Citations
... In the case of osteoid osteoma, anastomosing trabeculae of woven bone rimmed by osteoblasts with intervening capillary proliferation and benign giant cells are seen while osteolipoma shows mature adipose tissue and lamellar bone [12]. Cytogenetic aberrations that are translocation involving 12q13-15 might further aid in correct diagnosis, as 2/3 of lipomas exhibit genetic abnormalities which involved gene HMGA2 [13]. ...
Lipomas are the most common, subcutaneous, and slow-growing tumors composed of fat (adipose tissue). Out of many types of these benign tumors, ossifying lipoma (osteolipoma) is the rarest subtype. Here, randomly distributed trabeculae of lamellar bone are seen within mature adipose tissue. They are featured only as isolated case reports and small case series, thus the true incidence is not known. The most common site for osteolipoma is the head and neck region and they are rarely reported in the lower extremities. Herein, we discuss the case of a 19-year-old man who presented with a progressively enlarging painful mass in the left leg. Radiology was typical of osteoid osteoma. Excision was performed and histopathological examination confirmed the lesion as osteolipoma with no evidence of malignancy. No recurrence of the tumor was observed after 2 years of follow-up. Although osteolipoma is a rare entity, the differential diagnosis of the lesion can be kept in mind whenever we encounter ossification within the adipose tissue.
... (lipomas and pleomorphic adenomas) or with chromosome 9 open reading frame 92 (C9orf92) from 9p22, leading to HMGA2 truncation (50,51,126,127). On the other hand, the recurrent t(4;12)(q27~28;q14~15) chromosomal rearrangement in lipoma results in fusion of HMGA2 not with a gene but with various intergenic sequences from chromosome subband 4q28.1, again leading to truncation of HMGA2 (46). The above examples illustrate how chromosome translocations resulting in truncation of a gene may be viewed as recurrent variations on the same pathogenetic theme. ...
Chromosomal translocations in cancer as well as benign neoplasias typically lead to the formation of fusion genes. Such genes may encode chimeric proteins when two protein-coding regions fuse in-frame, or they may result in deregulation of genes via promoter swapping or translocation of the gene into the vicinity of a highly active regulatory element. A less studied consequence of chromosomal translocations is the fusion of two breakpoint genes resulting in an out-of-frame chimera. The breaks then occur in one or both protein-coding regions forming a stop codon in the chimeric transcript shortly after the fusion point. Though the latter genetic events and mechanisms at first awoke little research interest, careful investigations have established them as neither rare nor inconsequential. In the present work, we review and discuss the truncation of genes in neoplastic cells resulting from chromosomal rearrangements, especially from seemingly balanced translocations.
... This notwithstanding, many chromosomal rearrangements, such as balanced and unbalanced translocations, inversions, insertions, and deletions involving band 12q14 and targeting the HMGA2 gene have repeatedly been reported in lipomas and other benign neoplasms of connective tissues (40). In most cases, HMGA2 fuses out-of-frame with the 3'-end partner gene or with intergenic sequences (32,34,36,(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53). In these fusions, the part of the HMGA2 gene coding for the AT-hook domains, i.e., exons 1 to 3, is separated from the 3'-untranslated region which regulates HMGA2 transcription, resulting in expression and translation of a tumorigenic, truncated form of HMGA2 (54)(55)(56)(57)(58)(59)(60). ...
Background/aim:
Chimeras involving the high-mobility group AT-hook 2 gene (HMGA2 in 12q14.3) have been found in lipomas and other benign mesenchymal tumors. We report here a fusion of HMGA2 with the nuclear receptor co-repressor 2 gene (NCOR2 in 12q24.31) repeatedly found in tumors of bone and the first cytogenetic investigation of this fusion.
Materials and methods:
Six osteoclastic giant cell-rich tumors were investigated using G-banding, RNA sequencing, reverse transcription polymerase chain reaction, Sanger sequencing, and fluorescence in situ hybridization.
Results:
Four tumors had structural chromosomal aberrations of 12q. The pathogenic variant c.103_104GG>AT (p.Gly35Met) in the H3.3 histone A gene was found in a tumor without 12q aberration. In-frame HMGA2-NCOR2 fusion transcripts were found in all tumors. In two cases, the presence of an HMGA2-NCOR2 fusion gene was confirmed by FISH on metaphase spreads.
Conclusion:
Our results demonstrate that a subset of osteoclastic giant cell-rich tumors of bone are characterized by an HMGA2-NCOR2 fusion gene.
... Rearrangements of FOS and its fusion with various partners share similarities with rearrangements and fusions of the HMGA2 and CSF1 genes. In lipomas and other benign connective tissue tumors, chromosome aberrations, mainly translocations, disrupt the HMGA2 locus in 12q14 and fuse part of HMGA2 with various partners (10,(36)(37)(38)(39)(40)(41)(42). In all reported cases, the pattern is the same: Disruption of the HMGA2 locus leaves intact exons 1-3 which encode the AThook domains separating them from the 3'-untranslated region of the gene (3'-UTR). ...
Background/aim:
Osteoblastoma is a rare benign tumor of the bones in which recurrent rearrangements of FOS have been found. Our aim was to investigate two osteoblastomas for possible genetic aberrations.
Materials and methods:
Cytogenetic, RNA sequencing, and molecular analyses were performed.
Results:
A FOS-ANKH transcript was found in the first tumor, whereas a FOS-RUNX2 was detected in the second. Exon 4 of FOS fused with sequences either from intron 1 of ANKH or intron 5 of RUNX2. The fusion events introduced a stop codon and removed sequences involved in the regulation of FOS.
Conclusion:
Rearrangements and fusions of FOS show similarities with those of HMGA2 (a feature of leiomyomas and lipomas) and CSF1 (tenosynovial giant cell tumors). The replacement of a 3'-untranslated region, controlling the gene's expression, by a new sequence is thus a common pathogenetic theme shared by FOS, HMGA2, and CSF1 in many benign connective tissue tumors.
... The translocation led to rearrangement of the HMGA2 gene fusing it with a sequence from chromosome band 5p13. This pattern of rearrangement is similar to what happens to HMGA2 in other and more common connective tissue tumors, i.e. disruption of the HMGA2 locus leaving intact exons 1-3 which encode the AT-hook domains separating them from the 3'-untranslated region of the gene (3'-UTR) (25,(32)(33)(34). The 3'-UTR of HMGA2 has been shown to regulate transcription of the gene (35,36). ...
Background/aim:
Myoid hamartoma of the breast is a very rare benign lesion of which only a few cases have been reported. The pathogenesis is unknown and nothing is known about its genetic constitution. We report here the genetic characterization of a myoid hamartoma of the breast.
Materials and methods:
Cytogenetic, fluorescence in situ hybridization (FISH), RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), and Sanger sequencing analyses were performed on a myoid hamartoma of the breast.
Results:
G-Banding analysis of short-term cultured tumor cells yielded the karyotype 46,XX,t(5;12)(p13;q14)[6]/46,XX[4]. FISH showed rearrangement of the high mobility group AT-hook 2 (HMGA2) gene. RNA sequencing detected fusion of HMGA2 (12q14) with a sequence from 5p13. RT-PCR together with Sanger sequencing verified the HMGA2-fusion transcript.
Conclusion:
Myoid hamartoma of the breast may be pathogenetically related to benign connective tissue tumors with HMGA2 rearrangements, such as pulmonary hamartomas, lipomas, myolipomas, and leiomyomas.
... They are usually expressed during embryonic development [15,16] but not in adult normal tissues [17]. The genes were found overexpressed and/or targeted as part of the pathogenesis of many different tumours, both benign [18] and malignant [19], including mesenchymal [20] and epithelial [21] ones. HMGA proteins are involved in different pathogenic processes, but exert their main tumourigenic effect activating and sustaining epithelial-mesenchymal transition (EMT) [22]. ...
... Interestingly, HMGA2 was expressed at higher levels than its homologue in UCS as well as in OCS. The mechanisms of regulation of these Micci et al., 2004 two genes are not fully understood, but non-coding RNA dysregulation and chromosomal alterations are the two main causes leading to upregulation of HMGA1 and HMGA2 in cancer [18,20,23,24]. The HMGA1-targeting miRNAs let-7a [24], miR-26a [21], miR-16 [25], and miR-214 [26] were downregulated in CS of both sites in the present study, giving the impression that these cancers do not differ from other malignancies in this regard. ...
... We observed upregulation of HMGA2 with miRNA downregulation in both UCS and OCS, providing another piece of evidence that the interaction between the two is important also in gynaecological CS. Another indication pointing in the same direction has been the identification of disrupted forms of HMGA2, due to rearrangements of chromosomal band 12q15 (the band where the gene is located), that are consistently seen in different benign mesenchymal tumours but also in some malignant neoplasms such as ovarian carcinomas and leukemia [20,[33][34][35][36]. These alterations involve exon 3 and cause deletion of downstream regions leading to a truncated transcript that can evade miRNAdependent gene silencing. ...
Gynaecological carcinosarcomas are rare biphasic tumours which are highly aggressive. We performed molecular investigations on a series of such tumours arising in the uterus (n = 16) and ovaries (n = 10) to gain more information on their mutational landscapes and the expression status of the genes HMGA1/2, FHIT, LIN28A, and MTA1, the pseudogenes HMGA1P6 and HMGA1P7, and the miRNAs known to influence expression of the above-mentioned genes. In uterine carcinosarcomas (UCS), we identified mutations in KRAS, PIK3CA, and TP53 with a frequency of 6%, 31%, and 75%, respectively, whereas in ovarian carcinosarcomas (OCS), TP53 was the only mutated gene found (30%). An inverse correlation was observed between overexpression of HMGA1/2, LIN28A, and MTA1 and downregulation of miRNAs such as let-7a, let-7d, miR26a, miR16, miR214, and miR30c in both UCS and OCS. HMGA2 was expressed in its full length in 14 UCS and 9 OCS; in the remaining tumours, it was expressed in its truncated form. Because FHIT was normally expressed while miR30c was downregulated, not both downregulated as is the case in several other carcinomas, alterations of the epithelial-mesenchymal transition through an as yet unknown mechanism seems to be a feature of carcinosarcomas.
Background/aim:
Lipomas are benign tumors composed of mature fat cells. They are common soft tissue tumors that often carry chromosome aberrations involving 12q14 resulting in rearrangements, deregulation, and generation of chimeras of the high-mobility group AT-hook 2 gene (HMGA2) which maps in 12q14.3. In the present study, we report the finding of t(9;12)(q33;q14) translocation in lipomas and describe its molecular consequences.
Materials and methods:
Four lipomas from two male and two female adult patients were selected because their neoplastic cells carried a t(9;12)(q33;q14) as the sole karyotypic aberration. The tumors were investigated using RNA sequencing, reverse transcription polymerase chain reaction (RT-PCR), and Sanger sequencing techniques.
Results:
RNA sequencing of a t(9;12)(q33;q14)-lipoma detected an in-frame fusion of HMGA2 with the gelsolin gene (GSN) from 9q33. RT-PCR together with Sanger sequencing confirmed the presence of an HMGA2::GSN chimera in the tumor as well as in two other tumors from which RNA was available. The chimera was predicted to code for an HMGA2::GSN protein which would contain the three AT-hook domains of HMGA2 and the entire functional part of GSN.
Conclusion:
t(9;12)(q33;q14) is a recurrent cytogenetic aberration in lipomas and generates an HMGA2::GSN chimera. Similar to what is seen in other rearrangements of HMGA2 in mesenchymal tumors, the translocation physically separates the part of HMGA2 encoding AT-hook domains from the gene's 3'-terminal part which contains elements that normally regulate HMGA2 expression.
Uterine lipoleiomyomas are variants of uterine leiomyomas and are characterized by progressive enlargement that can occur even after menopause. These tumors can produce serious clinical symptoms and are difficult to diagnosis preoperatively. The growth rate of uterine lipoleiomyomas after menopause is comparatively higher than that of conventional uterine leiomyomas, and lipoleiomyosarcomas as well as tumor-to-tumor metastasis associated with lipoleiomyomas have been reported. However, detailed histogenic mechanisms of the tumor remain unclear. Surgical treatments are the current choice for the management of lipoleiomyomas. The purpose of this review is to promote greater awareness of lipoleiomyoma characteristics with a focus on histogenesis, diagnosis, and treatment. We performed an exhaustive literature review and have summarized the available data. We assessed the interpretation of auxiliary examinations to help physicians in making an early accurate diagnosis of the disease and to help with treatment decision-making, particularly regarding whether surgery should be performed or avoided.
