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Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions
Sarcomas are driven by diverse pathogenic mechanisms, including gene rearrangements in a subset of cases. Rare soft tissue sarcomas containing KMT2A fusions have recently been reported, characterized by a predilection for young adults, sclerosing epithelioid fibrosarcoma-like morphology, and an ofte...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581494/ https://www.ncbi.nlm.nih.gov/pubmed/32461620 http://dx.doi.org/10.1038/s41379-020-0582-4 |
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author | Massoth, Lucas R. Hung, Yin P. Nardi, Valentina Nielsen, G. Petur Hasserjian, Robert P. Louissaint, Abner Fisch, Adam S. Deshpande, Vikram Zukerberg, Lawrence R. Lennerz, Jochen K. Selig, Martin Glomski, Krzysztof Patel, Parth J. Williams, Kevin Jon Sokol, Ethan S. Alexander, Brian M. Vergilio, Jo-Anne Ross, Jeffrey S. Pavlick, Dean C. Chebib, Ivan Williams, Erik A. |
author_facet | Massoth, Lucas R. Hung, Yin P. Nardi, Valentina Nielsen, G. Petur Hasserjian, Robert P. Louissaint, Abner Fisch, Adam S. Deshpande, Vikram Zukerberg, Lawrence R. Lennerz, Jochen K. Selig, Martin Glomski, Krzysztof Patel, Parth J. Williams, Kevin Jon Sokol, Ethan S. Alexander, Brian M. Vergilio, Jo-Anne Ross, Jeffrey S. Pavlick, Dean C. Chebib, Ivan Williams, Erik A. |
author_sort | Massoth, Lucas R. |
collection | PubMed |
description | Sarcomas are driven by diverse pathogenic mechanisms, including gene rearrangements in a subset of cases. Rare soft tissue sarcomas containing KMT2A fusions have recently been reported, characterized by a predilection for young adults, sclerosing epithelioid fibrosarcoma-like morphology, and an often aggressive course. Nonetheless, clinicopathologic and molecular descriptions of KMT2A-rearranged sarcomas remain limited. In this study, we identified by targeted next-generation RNA sequencing an index patient with KMT2A fusion-positive soft tissue sarcoma. In addition, we systematically searched for KMT2A structural variants in a comprehensive genomic profiling database of 14,680 sarcomas interrogated by targeted next-generation DNA and/or RNA sequencing. We characterized the clinicopathologic and molecular features of KMT2A fusion-positive sarcomas, including KMT2A breakpoints, rearrangement partners, and concurrent genetic alterations. Collectively, we identified a cohort of 34 sarcomas with KMT2A fusions (0.2%), and YAP1 was the predominant partner (n = 16 [47%]). Notably, a complex rearrangement with YAP1 consistent with YAP1–KMT2A–YAP1 fusion was detected in most cases, with preservation of KMT2A CxxC-binding domain in the YAP1–KMT2A–YAP1 fusion and concurrent deletions of corresponding exons in KMT2A. The tumors often affected younger adults (age 20–66 [median 40] years) and histologically showed variably monomorphic epithelioid-to-spindle shaped cells embedded in a dense collagenous stroma. Ultrastructural evidence of fibroblastic differentiation was noted in one tumor examined. Our cohort also included two sarcomas with VIM–KMT2A fusions, each harboring concurrent mutations in CTNNB1, SMARCB1, and ARID1A and characterized histologically by sheets of spindle-to-round blue cells. The remaining 16 KMT2A-rearranged sarcomas in our cohort exhibited diverse histologic subtypes, each with unique novel fusion partners. In summary, KMT2A-fusion-positive sarcomas most commonly exhibit sclerosing epithelioid fibrosarcoma-like morphology and complex YAP1–KMT2A–YAP1 fusions. Cases also include rare spindle-to-round cell sarcomas with VIM–KMT2A fusions and tumors of diverse histologic subtypes with unique KMT2A fusions to non-YAP1 non-VIM partners. |
format | Online Article Text |
id | pubmed-7581494 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-75814942020-11-02 Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions Massoth, Lucas R. Hung, Yin P. Nardi, Valentina Nielsen, G. Petur Hasserjian, Robert P. Louissaint, Abner Fisch, Adam S. Deshpande, Vikram Zukerberg, Lawrence R. Lennerz, Jochen K. Selig, Martin Glomski, Krzysztof Patel, Parth J. Williams, Kevin Jon Sokol, Ethan S. Alexander, Brian M. Vergilio, Jo-Anne Ross, Jeffrey S. Pavlick, Dean C. Chebib, Ivan Williams, Erik A. Mod Pathol Article Sarcomas are driven by diverse pathogenic mechanisms, including gene rearrangements in a subset of cases. Rare soft tissue sarcomas containing KMT2A fusions have recently been reported, characterized by a predilection for young adults, sclerosing epithelioid fibrosarcoma-like morphology, and an often aggressive course. Nonetheless, clinicopathologic and molecular descriptions of KMT2A-rearranged sarcomas remain limited. In this study, we identified by targeted next-generation RNA sequencing an index patient with KMT2A fusion-positive soft tissue sarcoma. In addition, we systematically searched for KMT2A structural variants in a comprehensive genomic profiling database of 14,680 sarcomas interrogated by targeted next-generation DNA and/or RNA sequencing. We characterized the clinicopathologic and molecular features of KMT2A fusion-positive sarcomas, including KMT2A breakpoints, rearrangement partners, and concurrent genetic alterations. Collectively, we identified a cohort of 34 sarcomas with KMT2A fusions (0.2%), and YAP1 was the predominant partner (n = 16 [47%]). Notably, a complex rearrangement with YAP1 consistent with YAP1–KMT2A–YAP1 fusion was detected in most cases, with preservation of KMT2A CxxC-binding domain in the YAP1–KMT2A–YAP1 fusion and concurrent deletions of corresponding exons in KMT2A. The tumors often affected younger adults (age 20–66 [median 40] years) and histologically showed variably monomorphic epithelioid-to-spindle shaped cells embedded in a dense collagenous stroma. Ultrastructural evidence of fibroblastic differentiation was noted in one tumor examined. Our cohort also included two sarcomas with VIM–KMT2A fusions, each harboring concurrent mutations in CTNNB1, SMARCB1, and ARID1A and characterized histologically by sheets of spindle-to-round blue cells. The remaining 16 KMT2A-rearranged sarcomas in our cohort exhibited diverse histologic subtypes, each with unique novel fusion partners. In summary, KMT2A-fusion-positive sarcomas most commonly exhibit sclerosing epithelioid fibrosarcoma-like morphology and complex YAP1–KMT2A–YAP1 fusions. Cases also include rare spindle-to-round cell sarcomas with VIM–KMT2A fusions and tumors of diverse histologic subtypes with unique KMT2A fusions to non-YAP1 non-VIM partners. Nature Publishing Group US 2020-05-27 2020 /pmc/articles/PMC7581494/ /pubmed/32461620 http://dx.doi.org/10.1038/s41379-020-0582-4 Text en © The Author(s) 2020 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/. |
spellingShingle | Article Massoth, Lucas R. Hung, Yin P. Nardi, Valentina Nielsen, G. Petur Hasserjian, Robert P. Louissaint, Abner Fisch, Adam S. Deshpande, Vikram Zukerberg, Lawrence R. Lennerz, Jochen K. Selig, Martin Glomski, Krzysztof Patel, Parth J. Williams, Kevin Jon Sokol, Ethan S. Alexander, Brian M. Vergilio, Jo-Anne Ross, Jeffrey S. Pavlick, Dean C. Chebib, Ivan Williams, Erik A. Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions |
title | Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions |
title_full | Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions |
title_fullStr | Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions |
title_full_unstemmed | Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions |
title_short | Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions |
title_sort | pan-sarcoma genomic analysis of kmt2a rearrangements reveals distinct subtypes defined by yap1–kmt2a–yap1 and vim–kmt2a fusions |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581494/ https://www.ncbi.nlm.nih.gov/pubmed/32461620 http://dx.doi.org/10.1038/s41379-020-0582-4 |
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