Insertion of the CXXC domain of KMT2A into YAP1: An unusual mechanism behind the formation of a chimeric oncogenic protein

Gabriel Teku, Jenny Nilsson, Linda Magnusson, Saskia Sydow, Uta Flucke, Florian Puls, Shamik Mitra, Fredrik Mertens

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

Sammanfattning

Most neoplasia-associated gene fusions are formed through the fusion of the 5′-part of one gene with the 3′-part of another. We here describe a unique mechanism, by which a part of the KMT2A gene through an insertion replaces part of the YAP1 gene. The resulting YAP1::KMT2A::YAP1 (YKY) fusion was verified by RT-PCR in three cases of sarcoma morphologically resembling sclerosing epithelioid fibrosarcoma (SEF-like sarcoma). In all cases, a portion (exons 4/5–6) encoding the CXXC domain of KMT2A was inserted between exon 4/5 and exon 8/9 of YAP1. The inserted sequence from KMT2A thus replaced exons 5/6–8 of YAP1, which encode an important regulatory sequence of YAP1. To evaluate the cellular impact of the YKY fusion, global gene expression profiles from fresh frozen and formalin-fixed YKY-expressing sarcomas were compared with control tumors. The effects of the YKY fusion, as well as YAP1::KMT2A and KMT2A::YAP1 fusion constructs, were further studied in immortalized fibroblasts. Analysis of differentially upregulated genes revealed significant overlap between tumors and cell lines expressing YKY, as well as with previously reported YAP1 fusions. Pathway analysis of upregulated genes in cells and tumors expressing YKY revealed an enrichment of genes included in key oncogenic signaling pathways, such as Wnt and Hedgehog. As these pathways are known to interact with YAP1, it seems likely that the pathogenesis of sarcomas with the YKY fusion is linked to distorted YAP1 signaling.

Originalspråkengelska
Sidor (från-till)633-640
TidskriftGenes Chromosomes and Cancer
Volym62
Nummer11
DOI
StatusPublished - 2023

Ämnesklassifikation (UKÄ)

  • Medicinsk genetik

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