High-sensitive clinical diagnostic method for PTPRZ1-MET and the characteristic protein structure contributing to ligand-independent MET activation.
High-sensitive clinical diagnostic method for PTPRZ1-MET and the characteristic protein structure contributing to ligand-independent MET activation.
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DOI：
10.1111/cns.13627
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发表时间：
2021-05
影响因子：
5.5
通讯作者：
Hu H
中科院分区：
文献类型：
--
作者：
Huang R;Liu Y;Wang K;Wang Z;Zhang C;Zhang W;Zhao Z;Li G;Huang L;Chang Y;Zeng F;Jiang T;Hu H
PTPRZ 1-MET（ZM）是一种关键的遗传改变，可驱动低级别胶质瘤的进展。携带ZM的胶质瘤患者可以从MET抑制剂中获益。根据ZM作为胶质瘤进展的驱动因素和MET抑制剂敏感性的指标的显著作用，即使当其以相对较少的拷贝存在于胶质瘤中时，也有必要检测这种改变。在此，我们提出可以用具有50个扩增循环的高灵敏度逆转录酶PCR方法检测ZM。通过这种新提出的检测方法，我们描述了485例胶质瘤患者队列中ZM融合的发生率偏好。为了进一步探讨ZM的致癌本质，我们预测了其融合伴侣引起的MET激酶蛋白结构的改变。ZM融合的发生率远高于以前的报道。ZM融合在低级别胶质瘤和继发性胶质母细胞瘤中表现出明显的偏好。相比之下，原发性胶质母细胞瘤患者均未检测到ZM融合。在ZM的四种变体中的每一种中，MET的融合伴侣片段包含显著的卷曲螺旋基序。在表达ZM的胶质瘤细胞中，MET激酶可以以配体非依赖性方式被激活，这可能是由融合伴侣带来的特殊卷曲螺旋结构所促成的。与三维结构分析和细胞系实验相对应，ZM阳性临床标本显示MET信号过度激活。 ZM融合是胶质瘤进展的关键驱动因素和MET抑制剂的有效靶点。早期检测可以用高灵敏度的逆转录酶PCR方法进行。MET信号传导的过度激活驱动胶质瘤进展可能是由ZM融合体中MET胞外结构域的蛋白质结构修饰所实现的配体非依赖性激活所促成的。术后提取胶质瘤组织RNA。然后用基于所有四种ZM融合变体共有的PTPRZ 1和MET片段设计的引物进行50个扩增循环的RT-PCR。不同ZM变体的PCR产物具有不同的大小。将琼脂糖凝胶上的所有PCR产物条带纯化并通过桑格测序进行测序。将测序读数与已知的ZM融合序列进行比对。ZM融合体的存在和变异随后被证实和临床报道。
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. 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. 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. 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. Glioma tissue RNA was abstracted after surgery. RT‐PCR of 50 amplification cycles then was performed with the primers designed based on the PTPRZ1 and MET segments that are common to all the four ZM fusion variants. The PCR products of different ZM variants were of different sizes. All the PCR product bands on agarose gel were purified and sequenced via Sanger sequencing. The sequencing reads were aligned to the known ZM fusion sequences. The existence and the variant of ZM fusions then was confirmed and clinically reported.
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影响因子：
5.7
作者：
Olwill, Shane A.;Joffroy, Christian;Audoly, Laurent
通讯作者：
Audoly, Laurent
影响因子：
50.3
作者：
Mazor T;Pankov A;Johnson BE;Hong C;Hamilton EG;Bell RJA;Smirnov IV;Reis GF;Phillips JJ;Barnes MJ;Idbaih A;Alentorn A;Kloezeman JJ;Lamfers MLM;Bollen AW;Taylor BS;Molinaro AM;Olshen AB;Chang SM;Song JS;Costello JF
通讯作者：
Costello JF
影响因子：
64.8
作者：
通讯作者：
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影响因子：
64.5
作者：
Garrett, TPJ;McKern, NM;Ward, CW
通讯作者：
Ward, CW
272 例胶质瘤的 RNA 测序揭示了继发性胶质母细胞瘤中一种新的、复发性 PTPRZ1-MET 融合转录本。
影响因子：
7
作者：
Bao ZS;Chen HM;Yang MY;Zhang CB;Yu K;Ye WL;Hu BQ;Yan W;Zhang W;Akers J;Ramakrishnan V;Li J;Carter B;Liu YW;Hu HM;Wang Z;Li MY;Yao K;Qiu XG;Kang CS;You YP;Fan XL;Song WS;Li RQ;Su XD;Chen CC;Jiang T
通讯作者：
Jiang T