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Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature
Undifferentiated mesenchymal tumors arising from the inner lining (intima) of large arteries are classified as intimal sarcomas (ISA) with MDM2 amplification as their molecular hallmark. Interestingly, undifferentiated pleomorphic sarcomas (UPS) of the heart have recently been suggested to represent...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group US
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592836/ https://www.ncbi.nlm.nih.gov/pubmed/34312479 http://dx.doi.org/10.1038/s41379-021-00874-y |
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author | Koelsche, Christian Benhamida, Jamal K. Kommoss, Felix K. F. Stichel, Damian Jones, David T. W. Pfister, Stefan M. Heilig, Christoph E. Fröhling, Stefan Stenzinger, Albrecht Buslei, Rolf Mentzel, Thomas Baumhoer, Daniel Ladanyi, Marc Antonescu, Cristina R. Flucke, Uta Gorp, Joost van Bode-Lesniewska, Beata Deimling, Andreas von Mechtersheimer, Gunhild |
author_facet | Koelsche, Christian Benhamida, Jamal K. Kommoss, Felix K. F. Stichel, Damian Jones, David T. W. Pfister, Stefan M. Heilig, Christoph E. Fröhling, Stefan Stenzinger, Albrecht Buslei, Rolf Mentzel, Thomas Baumhoer, Daniel Ladanyi, Marc Antonescu, Cristina R. Flucke, Uta Gorp, Joost van Bode-Lesniewska, Beata Deimling, Andreas von Mechtersheimer, Gunhild |
author_sort | Koelsche, Christian |
collection | PubMed |
description | Undifferentiated mesenchymal tumors arising from the inner lining (intima) of large arteries are classified as intimal sarcomas (ISA) with MDM2 amplification as their molecular hallmark. Interestingly, undifferentiated pleomorphic sarcomas (UPS) of the heart have recently been suggested to represent the cardiac analog of ISA due to morphological overlap and high prevalence of MDM2 amplifications in both neoplasms. However, little is known about ISAs and cardiac UPS without MDM2 amplifications and molecular data supporting their common classification is sparse. Here, we report a series of 35 cases comprising 25 ISAs of the pulmonary artery, one ISA of the renal artery and 9 UPS of the left atrium. Tumors were analyzed utilizing the Illumina Infinium MethylationEPIC BeadChip array, enabling copy number profile generation and unsupervised DNA methylation analysis. DNA methylation patterns were investigated using t-distributed stochastic neighbor embedding (t-SNE) analysis. Histologically, all ISAs and UPS of the left atrium resembled extra-cardiac UPS. All cases exhibited highly complex karyotypes with overlapping patterns between ISA and UPS. 29/35 cases showed mutually exclusive amplifications in the cell-cycle associated oncogenes MDM2 (25/35), MDM4 (2/35), and CDK6 (2/35). We further observed recurrent co-amplifications in PDGFRA (21/35), CDK4 (15/35), TERT (11/35), HDAC9 (9/35), and CCND1 (4/35). Sporadic co-amplifications occurred in MYC, MYCN, and MET (each 1/35). The tumor suppressor CDKN2A/B was frequently deleted (10/35). Interestingly, DNA methylation profiling (t-SNE) revealed an overlap of ISA and cardiac UPS. This “ISA” methylation signature was distinct from potential histologic and molecular mimics. In conclusion, our data reveal MDM4 and CDK6 amplifications in ISAs and UPS of the left atrium, lacking MDM2 amplification. We further report novel co-amplifications of various oncogenes, which may have therapeutic implications. Finally, the genetic and epigenetic concordance of ISAs and UPS of the left atrium further supports a shared pathogenesis and common classification. |
format | Online Article Text |
id | pubmed-8592836 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-85928362021-11-23 Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature Koelsche, Christian Benhamida, Jamal K. Kommoss, Felix K. F. Stichel, Damian Jones, David T. W. Pfister, Stefan M. Heilig, Christoph E. Fröhling, Stefan Stenzinger, Albrecht Buslei, Rolf Mentzel, Thomas Baumhoer, Daniel Ladanyi, Marc Antonescu, Cristina R. Flucke, Uta Gorp, Joost van Bode-Lesniewska, Beata Deimling, Andreas von Mechtersheimer, Gunhild Mod Pathol Article Undifferentiated mesenchymal tumors arising from the inner lining (intima) of large arteries are classified as intimal sarcomas (ISA) with MDM2 amplification as their molecular hallmark. Interestingly, undifferentiated pleomorphic sarcomas (UPS) of the heart have recently been suggested to represent the cardiac analog of ISA due to morphological overlap and high prevalence of MDM2 amplifications in both neoplasms. However, little is known about ISAs and cardiac UPS without MDM2 amplifications and molecular data supporting their common classification is sparse. Here, we report a series of 35 cases comprising 25 ISAs of the pulmonary artery, one ISA of the renal artery and 9 UPS of the left atrium. Tumors were analyzed utilizing the Illumina Infinium MethylationEPIC BeadChip array, enabling copy number profile generation and unsupervised DNA methylation analysis. DNA methylation patterns were investigated using t-distributed stochastic neighbor embedding (t-SNE) analysis. Histologically, all ISAs and UPS of the left atrium resembled extra-cardiac UPS. All cases exhibited highly complex karyotypes with overlapping patterns between ISA and UPS. 29/35 cases showed mutually exclusive amplifications in the cell-cycle associated oncogenes MDM2 (25/35), MDM4 (2/35), and CDK6 (2/35). We further observed recurrent co-amplifications in PDGFRA (21/35), CDK4 (15/35), TERT (11/35), HDAC9 (9/35), and CCND1 (4/35). Sporadic co-amplifications occurred in MYC, MYCN, and MET (each 1/35). The tumor suppressor CDKN2A/B was frequently deleted (10/35). Interestingly, DNA methylation profiling (t-SNE) revealed an overlap of ISA and cardiac UPS. This “ISA” methylation signature was distinct from potential histologic and molecular mimics. In conclusion, our data reveal MDM4 and CDK6 amplifications in ISAs and UPS of the left atrium, lacking MDM2 amplification. We further report novel co-amplifications of various oncogenes, which may have therapeutic implications. Finally, the genetic and epigenetic concordance of ISAs and UPS of the left atrium further supports a shared pathogenesis and common classification. Nature Publishing Group US 2021-07-26 2021 /pmc/articles/PMC8592836/ /pubmed/34312479 http://dx.doi.org/10.1038/s41379-021-00874-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Koelsche, Christian Benhamida, Jamal K. Kommoss, Felix K. F. Stichel, Damian Jones, David T. W. Pfister, Stefan M. Heilig, Christoph E. Fröhling, Stefan Stenzinger, Albrecht Buslei, Rolf Mentzel, Thomas Baumhoer, Daniel Ladanyi, Marc Antonescu, Cristina R. Flucke, Uta Gorp, Joost van Bode-Lesniewska, Beata Deimling, Andreas von Mechtersheimer, Gunhild Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature |
title | Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature |
title_full | Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature |
title_fullStr | Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature |
title_full_unstemmed | Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature |
title_short | Intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive MDM2, MDM4, and CDK6 amplifications and share a common DNA methylation signature |
title_sort | intimal sarcomas and undifferentiated cardiac sarcomas carry mutually exclusive mdm2, mdm4, and cdk6 amplifications and share a common dna methylation signature |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592836/ https://www.ncbi.nlm.nih.gov/pubmed/34312479 http://dx.doi.org/10.1038/s41379-021-00874-y |
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