<i>Let‐7</i> MicroRNA and <i>HMGA2</i> levels of expression are not inversely linked in adipocytic tumors: Analysis of 56 lipomas and liposarcomas with molecular cytogenetic data

Bianchini, Laurence; Saâda, Esma; Gjernes, Elisabet; Marty, Marion; Haudebourg, Juliette; Birtwisle-Peyrottes, Isabelle; Keslair, Frédérique; Chignon-Sicard, Bérengère; Chamorey, Emmanuel; Pédeutour, Florence

doi:10.1002/gcc.20869

Cited by 20 publications

(22 citation statements)

References 45 publications

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“…When we started this study, information about the genomic status of HMGA2 in liposarcoma was scarce. A high frequency of the amplification of HMGA2 in well-differentiated liposarcoma had indeed been reported by our group 5,19 and by others. 6,10,21 Altogether, the available data had been obtained by heterogeneous methods including FISH, 5,19,22 qRT-PCR, 19 Southern blotting, 21 or CGH, 6 and the total number of patients studied was small.…”

Section: Discussionsupporting

confidence: 82%

“…A high frequency of the amplification of HMGA2 in well-differentiated liposarcoma had indeed been reported by our group 5,19 and by others. 6,10,21 Altogether, the available data had been obtained by heterogeneous methods including FISH, 5,19,22 qRT-PCR, 19 Southern blotting, 21 or CGH, 6 and the total number of patients studied was small. Here, we used FISH in a large series of 116 atypical lipomatous tumors/well-differentiated liposarcomas and dedifferentiated liposarcomas and we demonstrated that amplification of HMGA2 was significantly associated with atypical lipomatous tumor/well-differentiated liposarcoma, whereas the absence of amplification of HMGA2 was associated with dedifferentiated liposarcoma.…”

Section: Discussionsupporting

confidence: 82%

“…We also confirmed that the exons 1-3 of HMGA2-which encode the three DNA AT-hook-binding domains-were more frequently amplified compared with exons 4-5 (88% vs 76%). 5,19 Importantly, it has been previously shown that the expression of a truncated form of HMGA2 that retained only the three DNA-binding domains was sufficient to induce malignant transformation of fibroblasts. 32 More recently, Taylor et al 33 studied the genome, exome, transcriptome, and methylome of primary and recurrent cases of dedifferentiated liposarcomas and showed that HMGA2 lacked its 3′-UTR in both tumors.…”

Section: Discussionmentioning

confidence: 99%

“…19 Genomic amplification was defined as the presence of at least 10 fluorescent signals (grouped in clusters) per cell in ≥ 1% of cells. Genomic gain was defined as the presence of an average of~3-9 fluorescent signals evaluated in the same conditions.…”

Section: Molecular Cytogenetic Analysismentioning

confidence: 99%

“…19,20 The staining was considered as positive when at least one cell nucleus per high-power field was strongly stained.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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Prognostic value of HMGA2, CDK4, and JUN amplification in well-differentiated and dedifferentiated liposarcomas

et al. 2015

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HMGA2, CDK4, and JUN genes have been described as frequently coamplified with MDM2 in atypical lipomatous tumor, well-differentiated liposarcoma, and dedifferentiated liposarcoma. We studied the frequency of amplification of these genes in a series of 48 dedifferentiated liposarcomas and 68 atypical lipomatous tumors/well-differentiated liposarcomas. We correlated their amplification status with clinicopathological features and outcomes. Histologically, both CDK4 (P = 0.007) and JUN (P = 0.005) amplifications were associated with dedifferentiated liposarcoma, whereas amplification of the proximal parts of HMGA2 (5′-untranslated region (UTR) and exons 1-3) was associated with atypical lipomatous tumor/well-differentiated liposarcoma (P = 0.01). CDK4 amplification was associated with axial tumors. Amplification of 5′-UTR and exons 1-3 of HMGA2 was associated with primary status and grade 1. Shorter overall survival was correlated with: age 464 years (P = 0.03), chemotherapy used in first intent (Po0.001), no surgery (P = 0.003), grade 3 (Po0.001), distant metastasis (Po0.001), node involvement (P = 0.006), and CDK4 amplification (P = 0.07). In multivariate analysis, distant metastasis (HR = 8.8) and grade 3 (HR = 18.2) were associated with shorter overall survival. A shorter recurrence-free survival was associated with dedifferentiated liposarcoma (Po0.001), grade 3 (Po0.001), node involvement (Po0.001), distant metastasis (P = 0.02), recurrent status (P = 0.009), axial location (P = 0.001), and with molecular features such as CDK4 (P = 0.05) and JUN amplification (P = 0.07). Amplification of 5′-UTR and exons 1-3 (P = 0.08) and 3′-UTR (P = 0.01) of HMGA2 were associated with longer recurrence-free survival. Distant metastasis was associated with shorter recurrence-free survival (HR = 5.8) in multivariate analysis. Dedifferentiated liposarcoma type was associated with axial location, grade 3 and recurrent status. In conclusion, we showed that the amplification of HMGA2 was associated with the atypical lipomatous tumor/well-differentiated liposarcoma histological type and a good prognosis, whereas CDK4 and JUN amplifications were associated with dedifferentiated liposarcoma histology and a bad prognosis. In addition, we also provided the first description of the molecular evolution of a well-differentiated liposarcoma into four successive dedifferentiated liposarcoma relapses, which was consistent with our general observations.

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Section: Discussionsupporting

confidence: 82%

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Molecular Cytogenetic Analysismentioning

confidence: 99%

“…19,20 The staining was considered as positive when at least one cell nucleus per high-power field was strongly stained.…”

Section: Immunohistochemistrymentioning

confidence: 99%

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Prognostic value of HMGA2, CDK4, and JUN amplification in well-differentiated and dedifferentiated liposarcomas

et al. 2015

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Identification of PPAP2B as a novel recurrent translocation partner gene of HMGA2 in lipomas

Bianchini

Birtwisle

Saâda

et al. 2013

Genes Chromosomes & Cancer

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Most lipomas are characterized by translocations involving the HMGA2 gene in 12q14.3. These rearrangements lead to the fusion of HMGA2 with an ectopic sequence from the translocation chromosome partner. Only five fusion partners of HMGA2 have been identified in lipomas so far. The identification of novel fusion partners of HMGA2 is important not only for diagnosis in soft tissue tumors but also because these genes might have an oncogenic role in other tumors. We observed that t(1;12)(p32;q14) was the second most frequent translocation in our series of lipomas after t(3;12)(q28;q14.3). We detected overexpression of HMGA2 mRNA and protein in all t(1;12)(p32;q14) lipomas. We used a fluorescence in situ hybridization-based positional cloning strategy to characterize the 1p32 breakpoint. In 11 cases, we identified PPAP2B, a member of the lipid phosphate phosphatases family as the 1p32 target gene. Reverse transcription-polymerase chain reaction analysis followed by nucleotide sequencing of the fusion transcript indicated that HMGA2 3' untranslated region (3'UTR) fused with exon 6 of PPAP2B in one case. In other t(1;12) cases, the breakpoint was extragenic, located in the 3'region flanking PPAP2B 3'UTR. Moreover, in one case showing a t(1;6)(p32;p21) we observed a rearrangement of PPAP2B and HMGA1, which suggests that HMGA1 might also be a fusion partner for PPAP2B. Our results also revealed that adipocytic differentiation of human mesenchymal stem cells derived from adipose tissue was associated with a significant decrease in PPAP2B mRNA expression suggesting that PPAP2B might play a role in adipogenesis.

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MicroRNA expression profiles distinguish liposarcoma subtypes and implicate miR-145 and miR-451 as tumor suppressors

et al. 2014

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Liposarcomas are rare, heterogeneous and malignant tumors that can be divided into four histological subtypes with different characteristics and clinical behavior. Treatment consists of surgery in combination with systemic chemotherapy, but nevertheless mortality rates are high. More insight into the biology of liposarcoma tumorigenesis is needed to devise novel therapeutic approaches. MicroRNAs (miRNAs) have been associated with carcinogenesis in many tumors and may function as tumor suppressor or oncogene. In this study we examined miRNA expression in an initial series of 57 human liposarcomas (including all subtypes), lipomas and normal fat by miRNA microarrays. Supervised hierarchical clustering of the most differentially expressed miRNAs (p < 0.0002) distinguished most liposarcoma subtypes and control tissues. The distinction between well differentiated liposarcomas and benign lipomas was blurred, suggesting these tumor types may represent a biological continuum. MiRNA signatures of liposarcoma subtypes were established and validated in an independent series of 58 liposarcomas and control tissues. The expression of the miR-143/145 and miR-144/451 cluster members was clearly reduced in liposarcomas compared to normal fat. Overexpression of miR-145 and miR-451 in liposarcoma cell lines decreased cellular proliferation rate, impaired cell cycle progression and induced apoptosis. In conclusion, we show that miRNA expression profiling can be used to discriminate liposarcoma subtypes, which can possibly aid in objective diagnostic decision making. In addition, our data indicate that miR-145 and miR-451 act as tumor suppressors in adipose tissue and show that re-expression of these miRNAs could be a promising therapeutic strategy for liposarcomas.Liposarcomas are one of the most common types of soft tissue sarcomas, representing 10-15% of all mesenchymal neoplasms.1,2 Liposarcomas are heterogeneous tumors from adipogenic origin that, according to the latest WHO classification, can be divided into four histological subtypes: well differentiated (i.e., atypical lipomatous tumor), dedifferentiated, myxoid/round cell and pleomorphic liposarcoma. These subtypes largely differ from each other in terms of pathogenesis, genetic alterations and clinical behavior.Well differentiated liposarcoma is the most common subtype (40%), which is frequently hard to distinguish from benign fat tumors, i.e. lipomas. Genetically they are characterized by supernumerary rings and giant chromosomes which involve amplification of the 12q13-15 chromosomal region, containing oncogenes like MDM2, CDK4 and HMGA2.4,5 Well differentiated liposarcoma is locally aggressive, but shows no potential to metastasize unless the tumor undergoes dedifferentiation to a high grade tumor. Transition into dedifferentiated liposarcoma usually occurs abruptly and predominantly in tumors located in the retroperitoneum. Dedifferentiated liposarcomas also occur frequently (40%), and are more aggressive than the well differentiated tumors they arise from.Myxoid lipo...

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Let‐7 MicroRNA and HMGA2 levels of expression are not inversely linked in adipocytic tumors: Analysis of 56 lipomas and liposarcomas with molecular cytogenetic data

Cited by 20 publications

References 45 publications

Prognostic value of HMGA2, CDK4, and JUN amplification in well-differentiated and dedifferentiated liposarcomas

Prognostic value of HMGA2, CDK4, and JUN amplification in well-differentiated and dedifferentiated liposarcomas

Identification of PPAP2B as a novel recurrent translocation partner gene of HMGA2 in lipomas

MicroRNA expression profiles distinguish liposarcoma subtypes and implicate miR-145 and miR-451 as tumor suppressors

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