HMGA2 is the partner of MDM2 in well‐differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon

Italiano, Antoîne; Bianchini, Laurence; Keslair, Frédérique; Bonnafous, Stéphanie; Cardot‐Leccia, Nathalie; Coindre, Jean‐Michel; Dumollard, Jean‐Marc; Hofman, Paul; Leroux, Agnès; Mainguéné, C; Peyrottes, Isabelle; Ranchère-Vince, Dominique; Terrier, Philippe; Tran, Albert; Gual, Philippe; Pédeutour, Florence

doi:10.1002/ijc.23380

Cited by 189 publications

(199 citation statements)

References 39 publications

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“…Most likely, the amplification of the locus containing MDM2 was selected for by overexpression of other genes, such as CDK4 or HMGA2. [32][33][34] Furthermore, contrary to common reports that TP53 Mut leads to accumulation of p53 protein, we found low p53 expression in these samples (Fig. 2).…”

Section: Discussioncontrasting

confidence: 99%

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Ohnstad¹,

Castro²,

Sun³

et al. 2012

Cancer

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BACKGROUND: Relatively few sarcomas harbor TP53 (tumor protein p53) mutations, but in many cases, amplification of MDM2 (murine double minute 2) effectively inactivate p53. The p53 pathway activity can also be affected by normal genetic variation. METHODS: The mutation status of TP53 and expression of MDM2, TP53, and their genetic variants SNP309 and R72P (Arg72Pro) were investigated in 125 sarcoma patient samples and 18 sarcoma cell lines. Association of the different genotypes and gene aberrations with chemotherapy response and survival, as well as response to MDM2 antagonists in vitro was evaluated. RESULTS: Twenty-two percent of the tumors had mutant TP53 and 20% MDM2 gene amplification. Patients with wild-type TP53 (TP53 Wt ) tumors had improved survival (P < .001) and TP53 Wt was an independent prognostic factor (hazard ratio ¼ 0.41; 95% confidence interval ¼ 0.23-0.74; P ¼ .03). Interestingly, there was a trend toward longer time to progression after chemotherapy for tumors with the apoptosis-prone p53 variant R72 (P ¼ .07), which was strongest with doxorubicin/ifosfamide-based regimens (P ¼ .01). Liposarcomas had low R72 frequency (33% versus 56%), but increased levels of MDM2 and MDM4 (51% and 11%, P < .001). MDM2 overexpression on a TP53 Wt background predicted better response to MDM2 antagonist Nutlin-3a, irrespective of R72P or SNP309 status. CONCLUSIONS: Improved survival after chemotherapy was found in patients with TP53 Wt tumors harboring the R72 variant. MDM2 overexpression in TP53 Wt tumors predicted good response to MDM2 antagonists, irrespective of R72P or SNP309 status. Thus, detailed TP53 and MDM2 genotype analyses prior to

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Section: Discussioncontrasting

confidence: 99%

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Ohnstad¹,

Castro²,

Sun³

et al. 2012

Cancer

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“…[20][21][22][23][24][25] In dedifferentiated liposarcoma, for instance, amplification of MDM2 is nearly always accompanied by CPM, HMGA2, and YEATS4 in the same amplicon, while CDK4 can sometimes have GLI1 and DDIT3 as the amplification partners. 26,27 These findings are similar to what has been observed in our adenosarcoma cases. Interestingly, the amplification of MDM2 and CDK4 seemed Chromosomal instability in adenosarcomas to be limited to the mesenchymal component, suggesting a non-neoplastic nature of the glandular component, consistent with the recent findings.…”

Section: Discussionsupporting

confidence: 91%

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Lee

Changou

et al. 2016

Modern Pathology

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Müllerian adenosarcomas are malignant gynecologic neoplasms. Advanced staging and sarcomatous overgrowth predict poor prognosis. Because the genomic landscape remains poorly understood, we conducted this study to characterize the genomewide copy number variations in adenosarcomas. Sixteen tumors, including eight with and eight without sarcomatous overgrowth, were subjected to a molecular inversion probe array analysis. Copy number variations, particularly losses, were significantly higher in cases with sarcomatous overgrowth. Frequent gains of chromosomal 12q were noted, often involving cancer-associated genes CDK4 (six cases), MDM2, CPM, YEATS4, DDIT3, GLI1 (five each), HMGA2 and STAT6 (four), without association with sarcomatous overgrowth status. The most frequent losses involved chromosomes 13q (five cases), 9p, 16q and 17q (four cases each) and were almost limited to cases with sarcomatous overgrowth. MDM2 and CDK4 amplification, as well as losses of RB1 (observed in two cases) and CDKN2A/B (one case), was verified by FISH. By immunohistochemistry, all MDM2/CDK4-coamplified cases were confirmed to overexpress both encoded proteins, whereas all four cases with (plus an additional four without) gain of HMGA2 overexpressed the HMGA2 protein. Both cases with RB1 loss were negative for the immunostaining of the encoded protein. Chromothripsis-like copy number profiles involving chromosome 12 or 14 were observed in three fatal cases, all of which harbored sarcomatous overgrowth. With whole chromosome painting and deconvolution fluorescent microscopy, dividing tumor cells in all three cases were shown to have scattered extrachromosomal materials derived from chromosomes involved by chromothripsis, suggesting that this phenomenon may serve as visual evidence for chromothripsis in paraffin

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“…Although the IFNG gene is supposed to be situated in between CDK4 and MDM2, these results, which could implicate two different amplicons, are in accordance with the results reported by others. [14][15][16] Multiplex ligation-dependant probe amplification of the primary extremity myxoid/round cell liposarcoma group showed, in 1 of 20 (5%) patients, an amplification (4.38) in one of the five probes targeting the 12q13-15 region.…”

Section: Amplification Of 12q13-15 By Multiplex Ligationdependant Promentioning

confidence: 99%

Primary retroperitoneal myxoid/round cell liposarcoma is a nonexisting disease: an immunohistochemical and molecular biological analysis

et al. 2009

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Almost all primary retroperitoneal liposarcomas can be classified as well-/dedifferentiated liposarcoma. Rarely, however, primary retroperitoneal liposarcoma is classified as myxoid/round cell liposarcoma, based on the presence of myxoid areas and vascular crow's feet pattern, which has resulted in a debate on the classification of liposarcoma in the retroperitoneum. Genetically, myxoid/round cell liposarcoma and well-/dedifferentiated liposarcoma are different diseases. Myxoid/round cell liposarcoma is characterized by a translocation causing FUS-CHOP or EWSR1-CHOP fusion, whereas well-/dedifferentiated liposarcoma is characterized by an amplification of the 12q13-15 region, including MDM2 and CDK4 genes. As myxoid/round cell liposarcoma is highly radio-and chemosensitive, differentiation between subtypes is important to optimize treatment. We studied whether primary retroperitoneal liposarcomas diagnosed as myxoid/round cell liposarcoma represent molecularly true myxoid/round cell liposarcoma or are histopathological mimics and represent well-/dedifferentiated liposarcoma. Primary retroperitoneal myxoid/round cell liposarcoma (n ¼ 16) were compared to primary extremity myxoid/round cell liposarcoma (n ¼ 20). Histopathological and immunohistochemical features were studied. Amplification status of the 12q13-15 region was studied using a multiplex ligation-dependent probe amplification analysis, and FUS-CHOP or EWS-CHOP translocations were studied using RT-PCR. In primary retroperitoneal myxoid/round cell liposarcoma, MDM2 and CDK4 staining was both positive in 12 of 15 cases. In primary extremity myxoid/round cell liposarcoma, MDM2 was negative in 18/20 and CDK4 was negative in all cases. Multiplex ligation-dependent probe amplification showed the amplification of 12q13-15 region in 16/16 primary retroperitoneal myxoid/round cell liposarcomas and in 1/20 primary extremity myxoid/round cell liposarcomas. Translocation was present in all (18/18) primary extremity myxoid/round cell liposarcomas, but absent in all primary retroperitoneal myxoid/round cell liposarcomas. On the basis of immunohistochemical and molecular characteristics, apparent primary retroperitoneal myxoid/round cell liposarcoma can be recognized as well-/dedifferentiated liposarcoma with morphological features mimicking myxoid/round cell liposarcoma. In these cases, treatment should probably be specifically designed as for well-/dedifferentiated liposarcoma. Moreover, finding of myxoid/round cell liposarcoma translocations in a retroperitoneal localization is highly suggestive of metastasis and should prompt search for a primary localization outside the retroperitoneum. Keywords: liposarcoma; retroperitoneal; myxoid/round cell; well-/dedifferentiated; RT-PCR; multiplex ligation-dependant probe amplification Liposarcomas are a rare type of malignancy with a very heterogeneous morphological appearance and clinical course. The therapeutic approach is based on histopathological classification and is dependent on primary localization.Liposarcoma occurs...

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HMGA2 is the partner of MDM2 in well‐differentiated and dedifferentiated liposarcomas whereas CDK4 belongs to a distinct inconsistent amplicon

Cited by 189 publications

References 39 publications

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Correlation of TP53 and MDM2 genotypes with response to therapy in sarcoma

Genomewide copy number analysis of Müllerian adenosarcoma identified chromosomal instability in the aggressive subgroup

Primary retroperitoneal myxoid/round cell liposarcoma is a nonexisting disease: an immunohistochemical and molecular biological analysis

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