PLAG1 alterations in lipoblastoma: involvement in varied mesenchymal cell types and evidence for alternative oncogenic mechanisms.

Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
American Journal Of Pathology (Impact Factor: 4.59). 10/2001; 159(3):955-62.
Source: PubMed


Lipoblastomas are rare soft tissue tumors that occur primarily in young children. They typically contain variably differentiated adipocytes, primitive mesenchymal cells, myxoid matrix, and fibrous trabeculae. Abnormalities in chromosome 8, leading to rearrangements of the PLAG1 gene, were demonstrated recently in four lipoblastomas. In the present report, we determine the frequency of PLAG1 alterations in 16 lipoblastomas from children aged 13 years or younger, and we also evaluate the stages of lipoblastoma differentiation at which PLAG1 genomic alterations are found. Eleven lipoblastomas (69%), including those with either classic or lipoma-like histology, had rearrangements of the 8q12 PLAG1 region. Another three lipoblastomas had polysomy for chromosome 8 in the absence of PLAG1 rearrangement. Only two cases (13%) lacked a chromosome 8 abnormality. Notably, the lipoblastomas with chromosome 8 polysomy had up to five copies of chromosome 8 as an isolated cytogenetic finding in an otherwise diploid cell. We also demonstrate that PLAG1 alterations are found in a spectrum of mesenchymal cell types in lipoblastomas, including lipoblasts, mature adipocytes, primitive mesenchymal cells, and fibroblast-like cells. This finding is consistent with neoplastic origin in a primitive mesenchymal precursor and with variable differentiation to a mature adipocyte end-point. Hence, our studies provide biological validation for the clinical observation that lipoblastomas can evolve into mature, lipoma-like, lesions. They also suggest that PLAG1 dosage alterations caused by polysomy 8 might represent an alternative oncogenic mechanism in lipoblastoma.

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Available from: Raf Sciot, Oct 04, 2015
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    • "In lipoblastomas, several chromosomal rearrangements have been described, involving the pleiomorphic adenoma gene 1 (PLAG1) oncogene. In particular, it was shown that the hyaluronic acid synthase 2 (HAS2) or collagen 1 α2 (COL1A2) gene promoter regions are fused to the entire PLAG1 coding sequence (4). The PLAG1 status was investigated through in situ hybridization techniques, particularly fluorescence detection [fluorescence in situ hybridization (FISH)] and chromogenic detection [chromogenic in situ hybridization (CISH)] (5). "
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    ABSTRACT: Approximately one third of soft tissue tumors are characterized by chromosomal aberrations, in particular, translocations and amplifications, which appear to be highly specific. The identification of fusion transcripts not only supports the diagnosis, but provides the basis for the development of novel therapeutic strategies aimed at blocking the aberrant activity of chimeric proteins. Molecular biology, and in particular, cytogenetic and qualitative and quantitative polymerase chain reaction technologies, allow with high efficiency and specificity, the determination of specific fusion transcripts resulting from chromosomal translocations, as well as the analysis of gene amplifications. In this review, various molecular techniques that allow the identification of translocations and consequent fusion transcripts generated are discussed in the broad spectrum of soft tissue tumors.
    International Journal of Molecular Medicine 04/2014; 33(6). DOI:10.3892/ijmm.2014.1726 · 2.09 Impact Factor
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    • "Chromosomal translocations affecting 12q14∼15 and targeting HMGA2 are a common finding in lipomas often as a t(3;12)(q27;q14∼15) [26], [27]. In contrast, translocations of 8q12 are a recurrent cytogenetic deviation in lipoblastomas, i. e. rare benign adipose tissue tumors of early childhood [19], [28]–[30]. Interestingly, pleomorphic adenomas and lipoblastomas share the most frequent type of this rearrangement, i.e. a simple reciprocal translocation t(3;8)(p21;q12). Recently, an infantile lipoblastoma with rearrangements of the HMGA2 locus has been described as well [31]. "
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    ABSTRACT: In pleomorphic adenomas of the salivary glands (PASG) recurrent chromosomal rearrangements affecting either 8q12 or 12q14∼15 lead to an overexpression of the genes of the genuine transcription factor PLAG1 or the architectural transcription factor HMGA2, respectively. Both genes are also affected by recurrent chromosomal rearrangements in benign adipocytic tumors as e. g. lipomas and lipoblastomas. Herein, we observed a strong correlation between the expression of HMGA2 and PLAG1 in 14 benign and 23 malignant thyroid tumors. To address the question if PLAG1 can be activated by HMGA2, the expression of both genes was quantified in 32 uterine leiomyomas 17 of which exhibited an overexpression of HMGA2. All leiomyomas with HMGA2 overexpression also revealed an activation of PLAG1 in the absence of detectable chromosome 8 abnormalities affecting the PLAG1 locus. To further investigate if the overexpression of PLAG1 is inducible by HMGA2 alone, HMGA2 was transiently overexpressed in MCF-7 cells. An increased PLAG1 expression was observed 24 and 48 h after transfection. Likewise, stimulation of HMGA2 by FGF1 in adipose tissue-derived stem cells led to a simultaneous increase of PLAG1 mRNA. Altogether, these data suggest that HMGA2 is an upstream activator of PLAG1. Accordingly, this may explain the formation of tumors as similar as lipomas and lipoblastomas resulting from an activation of either of both genes by chromosomal rearrangements.
    PLoS ONE 02/2014; 9(2):e88126. DOI:10.1371/journal.pone.0088126 · 3.23 Impact Factor
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    • "Lipoblastomas usually have simple, pseudodiploid karyotypes with structural chromosomal alterations. They are characterized by rearrangements of 8q11–13 involving the PLAG1 gene [35–38]. Excess copies of chromosome 8 may be found in cases with or without 8q11–13 rearrangements [10, 39]. "
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    ABSTRACT: Over the last 20 years, a number of tumor-specific chromosomal translocations and associated fusion genes have been identified for mesenchymal neoplasms including adipocytic tumors. The addition of molecular cytogenetic techniques, especially fluorescence in situ hybridization (FISH), has further enhanced the sensitivity and accuracy of detecting nonrandom chromosomal translocations and/or other rearrangements in adipocytic tumors. Indeed, most resent molecular cytogenetic analysis has demonstrated a translocation t(11;16)(q13;p13) that produces a C11orf95-MKL2 fusion gene in chondroid lipoma. Additionally, it is well recognized that supernumerary ring and/or giant rod chromosomes are characteristic for atypical lipomatous tumor/well-differentiated liposarcoma and dedifferentiated liposarcoma, and amplification of 12q13-15 involving the MDM2, CDK4, and CPM genes is shown by FISH in these tumors. Moreover, myxoid/round cell liposarcoma is characterized by a translocation t(12;16)(q13;p11) that fuses the DDIT3 and FUS genes. This paper provides an overview of the role of conventional cytogenetics and molecular cytogenetics in the diagnosis of adipocytic tumors.
    BioMed Research International 01/2011; 2011(1110-7243):524067. DOI:10.1155/2011/524067 · 2.71 Impact Factor
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