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

Abstract

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.

‘I Can’t Keep Up!’: an update on advances in soft tissue pathology occurring after the publication of the 2020 World Health Organization classification of soft tissue and bone tumours

“…Massoth et al . reported the clinicopathological and molecular genetic features of 34 KMT2A ‐rearranged sarcomas, culled from a comprehensive genomic profiling database of >14 000 sarcomas, with the largest subset (16 cases, 47%) harbouring fusions involving KMT2A and YAP1 11 . The demographic features and anatomical locations of these 16 tumours were similar to those reported by Kao et al .…”

“…Arguably, the classification of fibroblastic tumours has undergone the most significant changes over the past decade, with the rise and fall of solitary fibrous tumour and fibrosarcoma, respectively, 6 and the recognition of new morphologically and genetically distinctive entities, including angiofibroma of soft tissue, 7 superficial CD34‐positive fibroblastic tumour, 8 and EWSR1 :: SMAD3 fibroblastic tumour 9 . Very recently, two other distinctive subsets of fibroblastic tumour have been identified, characterised by rearrangements involving KMT2A 10–12 and PRRX :: NCOA1 / 2 fusions, 13 respectively.…”

“…Two more recent studies have also examined the clinicopathological features of KMT2A ‐rearranged soft tissue tumours 11,12 . Massoth et al .…”

Sclerosing epithelioid fibrosarcoma: in‐depth review of a genetically heterogeneous tumor

“…One case in that study showed PRRX1‐KMT2D gene fusion. In the same year, a study performed by Massoth et al [32] revealed that KMT2A ‐rearranged sarcomas commonly exhibit sclerosing epithelioid sarcoma‐like morphology and complex YAP1‐KMT2A‐YAP1 fusions, which provided another evidence that KMT2A gene rearrangement can occur in a subset of cases of SEF. In 2021, the largest reported series to date of 51 cases of SEF was performed by Warkme and Meis [33].…”

Molecular pathology of thymomas: implications for diagnosis and therapy

“…The function of the respective fusion proteins in thymomas is currently unclear, but might be oncogenic drivers, since 7 of the 11 cases did not harbor any concurrent mutations, while the four others showed only single additional mutations/variants in TP53 , ARID1A, SFB1 , and the TERT promoter [ 46 ]. Furthermore, KMT2A (also known as MLL) is a known oncogenic driver in translocations with other partner genes in sarcomas [ 47 ] and leukemias [ 46 ]. Since the index case of the series of Massoth et al was a recurrent B3 thymoma biopsied after chemotherapy, and the treatment status of the other cases was not reported, it is currently unclear, whether the KMT2A-MAML2 translocation is an early or late molecular event.…”