High‐sensitive clinical diagnostic method for PTPRZ1‐MET and the characteristic protein structure contributing to ligand‐independent MET activation

Abstract

Background PTPRZ1‐MET (ZM) is a critical genetic alteration driving the progression of lower‐grade glioma. Glioma patients harboring ZM could benefit from MET inhibitors. According to the remarkable role of ZM as a driver of glioma progression and indicator of MET inhibitor sensitivity, it is necessary to detect this alteration even when it presents in glioma with relatively fewer copies. Methods Herein, we proposed that ZM could be detected with a high‐sensitive method of reverse transcriptase PCR with 50 amplification cycles. Via this newly proposed detection method, we depicted the incidence preference of ZM fusion in a cohort of 485 glioma patients. To further explore the oncogenic nature of ZM, we predicated the protein structure alteration of MET kinase brought by its fusion partner. Results The incidence of ZM fusions was much higher than previous report. ZM fusions exhibited a striking preference in lower‐grade glioma and secondary glioblastoma. By contrast, none of patients with primary glioblastoma was detected harboring ZM fusion. In each of the four variants of ZM, the fusion partner segment of MET contained a remarkable coiled‐coil motif. In glioma cells expressing ZM, MET kinase could be activated in a ligand‐independent manner, which might be contributed by the special coiled‐coil structure brought by the fusion partner. Corresponding to the 3D structural analysis and cell line experiment, the ZM positive clinical specimens showed hyperactivations of MET signaling. Conclusions ZM fusions are critical drivers of glioma progression and effective target of MET inhibitor. Early detection could be performed with a high‐sensitive method of reverse transcriptase PCR. The hyperactivations of MET signaling driving glioma progression might be contributed by a ligand‐independent activation enabled by the protein structure modification of extracellular domain of MET in ZM fusions.

Detection of Novel Tyrosine Kinase Fusion Genes as Potential Therapeutic Targets in Bone and Soft Tissue Sarcomas Using DNA/RNA-based Clinical Sequencing

“…Kinase insert domain receptor fusion tumors showed very weak VEGFR2 expression, although VEGFR2 expression has been observed in synovial sarcoma and chordoma in patients with nonendothelial mesenchymal tumors [30]. Moreover, PTPRZ1-MET (P1, M2, P2, M2, P3, and M2) fusions were detected in tumors of the central nervous system [19], which covered almost the entire tyrosine kinase region, similar to the four tyrosine kinase fusions, VWC2-EGFR (V3; E2), ICK-KDR (I5; K2), FOXP2-MET (F2, M12), and CEP290-MET (C5, M12). A previous study showed there was ligand-independent phosphorylation of MET [19].…”

“…Moreover, PTPRZ1-MET (P1, M2, P2, M2, P3, and M2) fusions were detected in tumors of the central nervous system [19], which covered almost the entire tyrosine kinase region, similar to the four tyrosine kinase fusions, VWC2-EGFR (V3; E2), ICK-KDR (I5; K2), FOXP2-MET (F2, M12), and CEP290-MET (C5, M12). A previous study showed there was ligand-independent phosphorylation of MET [19]. Overexpression of C- MET was observed in patients with FOXP2-MET and CEP290-MET .…”

Multiomics integration reveals the effect of Orexin A on glioblastoma

“…[PMID:25853691 and PMID:34873473] ( Mallawaaratchy et al, 2015;Wei et al, 2021) Moreover, Wang Q. W et al (2021) suggested that the MET-STAT4-PD-L1 axis may act with tumor-associated macrophages to enhance immune escape in gliomas and cause poor prognosis in patients with GBM. And Huang et al (Huang R. et al, 2021) verified that PTPRZ1-MET (ZM) fusion was a key genetic change that drives the progression of low-grade glioma and helped ZM-carrying glioma patients benefit from MET inhibitors. In addition, the inhibition of receptor tyrosine kinases, including MET and/or its ligand hepatocyte growth factor (HGF), is a promising therapeutic strategy against tumor (Suzuki et al, 2010;Ge et al, 2013;Song et al, 2020).…”

Targeting gene fusions in glioma

“…The mechanism of fusion acquisition is unknown. Studies on the PTPRZ1–MET fusion show that the MET TRK is constitutively activated resulting in its oncogenic properties [33]. Further, MET fusions are sometimes paired with MET exon 14 skip mutations; this exon promotes degradation of MET suggesting the deletion of this exon promotes gliomagenesis.…”

“…This fusion transcript indicated a worse prognosis in these patients with overall survival being 239 days in fusion positive patients vs. 318 days in fusion-negative patients. This specific gene fusion was associated with patients age less than 40 years [33]. PTPRZ1–MET fusions have not been heavily studied in western populations.…”