<i>KMT2A</i> (<i>MLL</i>) fusions in aggressive sarcomas in young adults

Yoshida, Akihiko; Arai, Yasuhito; Tanzawa, Yoshikazu; Wakai, Susumu; Hama, Natsuko; Kawai, Akira; Shibata, Tatsuhiro

doi:10.1111/his.13926

Cited by 21 publications

(29 citation statements)

References 22 publications

(37 reference statements)

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“…This study augments the clinicopathologic descriptions of YAP1 – KMT2A fusion-positive sarcomas [ 3 , 4 , 6 ]. YAP1 – KMT2A fusion-positive sarcomas may behave aggressively, given the rapid decline in the index patient and the advanced tumor stage in most cases.…”

Section: Discussionsupporting

confidence: 60%

“…YAP1 – KMT2A fusion-positive sarcomas contained histologic patterns reminiscent of sclerosing epithelioid fibrosarcoma. While low-grade fibromyxoid sarcoma-like histology was noted in three of seven cases in one study [ 6 ], this was not observed in other studies [ 3 , 4 ]. Our histologic review, limited to a representative section in most cases, precluded full assessment of such “hybrid” features.…”

Section: Discussionmentioning

confidence: 68%

“…A limitation of our study is that the queried database is enriched for aggressive cases and advanced disease where genetic testing is desired for therapeutic target identification. From 11 patients with available follow-up in the three prior studies, three showed no recurrence after initial resection, five recurred locally or with unresectable tumors, and three harbored metastatic disease; altogether, three of 11 reported patients died of disease [ 3 , 4 , 6 ].…”

Section: Discussionmentioning

confidence: 99%

“…A fraction of sarcomas remain unclassified or difficult to classify based on histologic and immunohistochemical profile, with no putative driver mutation identified [ 2 ]. Recently, oncogenic rearrangements involving Lysine methyltransferase 2A ( KMT2A ), a frequent fusion partner in some acute leukemias, have been reported in solid tumors, including types B2 and B3 thymomas and soft tissue sarcomas [ 3 – 7 ]. Yoshida et al first described two soft tissue sarcomas with KMT2A rearrangements, one each to the partners yes-associated protein 1 ( YAP1) and vimentin ( VIM ) [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, oncogenic rearrangements involving Lysine methyltransferase 2A ( KMT2A ), a frequent fusion partner in some acute leukemias, have been reported in solid tumors, including types B2 and B3 thymomas and soft tissue sarcomas [ 3 – 7 ]. Yoshida et al first described two soft tissue sarcomas with KMT2A rearrangements, one each to the partners yes-associated protein 1 ( YAP1) and vimentin ( VIM ) [ 3 ]. Two subsequent studies described YAP1 as a recurrent fusion partner in KMT2A -rearranged sarcomas that showed histologic features reminiscent of sclerosing epithelioid fibrosarcoma, and in some cases, low-grade fibromyxoid sarcoma [ 4 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions

et al. 2020

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A molecular study of synovial chondromatosis

Agaram

Zhang

Dickson

et al. 2019

Genes Chromosomes & Cancer

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Synovial chondromatosis (SC) is a rare benign cartilaginous neoplasm in which recurrent fibronectin 1 (FN1) and activin receptor 2A (ACVR2A) gene rearrangements have been recently reported. Triggered by a case of malignant transformation in SC (synovial chondrosarcoma) showing a novel KMT2A‐BCOR gene fusion by targeted RNA sequencing, we sought to evaluate the molecular abnormalities in a cohort of 27 SC cases using a combined methodology of fluorescence in situ hybridization (FISH) and/or targeted RNA sequencing. Results showed that FN1 and /or ACVR2A gene rearrangements were noted in 18 cases (67%), with an FN1‐ACVR2A fusion being confirmed in 15 (56%) cases. Two cases showed only FN1 gene rearrangement, without other abnormalities. A novel FN1‐NFATc2 gene fusion was noted in one case by RNA sequencing. The remaining nine cases showed no abnormalities in FN1 and ACVR2A genes. No additional cases showed BCOR gene alterations. In conclusion, this study confirms that FN1‐ACVR2A fusion is the leading pathogenetic event in SC, at even higher frequency than previously reported. FISH methodology emerges as an appropriate tool in the identification of FN1 and ACVR2A gene abnormalities, which can be used in challenging cases. Further studies are needed to determine the recurrent potential of BCOR abnormalities in this disease.

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VIM::KMT2A‐rearranged sarcomas: A report of two new cases confirming an entity with distinct histologic features

Almohsen

Griffin

Dickson

et al. 2023

Genes Chromosomes & Cancer

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The recently described KMT2A‐rearranged sarcomas are rare emerging entities where the KMT2A gene fuses with YAP1 and, less commonly, VIM, resulting in two distinct morphologies. Unlike the sclerosing epithelioid fibrosarcoma‐like features that characterize tumors with KMT2A::YAP1 fusions, VIM::KMT2A‐rearranged sarcomas are more uniformly cellular and lack the extensively sclerotic background seen in the former. Most tumors behave aggressively with metastases on presentation. Here, we describe the clinicopathologic and molecular findings in two additional cases of VIM::KMT2A rearranged sarcomas that arose in the deep soft tissues of adult males. Both tumors were composed of hypercellular fascicles of uniform spindle cells with pale eosinophilic cytoplasm and ovoid nuclei. The stroma had scant delicate collagen with occasional thin‐walled ectatic blood vessels and perivascular hyalinization. Immunohistochemical studies showed an unspecific staining pattern with diffuse positivity for CD99 and BCL2 and variable staining for S100 protein. RNA‐sequencing detected the presence of VIM::KMT2A gene fusion involving VIM exon 4 and KMT2A exon 2 in both cases. Sarcomas with VIM::KMT2A gene fusions seem to have sufficient morphologic features to warrant distinction from KMT2A‐rearranged sarcomas with YAP1 partner. Without the benefit of molecular testing, these tumors pose a diagnostic challenge due to their lack of specific immunohistochemical profile and great morphologic overlap with other monomorphic spindle cell neoplasms.

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KMT2A (MLL) fusions in aggressive sarcomas in young adults

Cited by 21 publications

References 22 publications

Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions

Pan-sarcoma genomic analysis of KMT2A rearrangements reveals distinct subtypes defined by YAP1–KMT2A–YAP1 and VIM–KMT2A fusions

A molecular study of synovial chondromatosis

VIM::KMT2A‐rearranged sarcomas: A report of two new cases confirming an entity with distinct histologic features

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