Macher-Goeppinger Stephan, Keith Martina, Endris Volker, Penzel Roland, Tagscherer Katrin E, Pahernik Sascha, Hohenfellner Markus, Gardner Humphrey, Grüllich Carsten, Schirmacher Peter, Roth Wilfried
Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Molecular Tumor Pathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Oncotarget. 2017 Jan 3;8(1):1046-1057. doi: 10.18632/oncotarget.13540.
Multiple targeted therapy for advanced clear-cell renal cell carcinoma (RCC) has substantially improved patient outcome, but complete remission is uncommon and many tumors eventually develop resistance. Mechanistic, preclinical, and early clinical data highlight c-Met / hepatocyte growth factor receptor as a promising target for RCC therapeutic agents.We have examined MET expression, frequency of MET gene copy gains and MET gene mutation in a large, hospital-based series of renal cell carcinomas with long-term follow-up information.Out of a total of 572 clear-cell RCC, only 17% were negative for MET expression whereas 32% showed high protein levels. High MET expression and MET copy number gains were associated with an aggressive phenotype and an unfavorable patient outcome. Elevated protein levels in absence of gene amplification were not attributed to mutations, based on results of targeted next-generation sequencing.Our data reveal that clear-cell RCC with MET upregulation show an aggressive behavior and MET copy number increase is evident in a substantial percentage of patients with high-grade carcinomas and metastatic disease. Diagnostic assessment of MET expression and amplification may be of predictive value to guide targeted therapy against MET signaling in patients with clear-cell RCC.
晚期肾透明细胞癌（RCC）的多靶点治疗显著改善了患者的预后，但完全缓解并不常见，许多肿瘤最终会产生耐药性。机制、临床前和早期临床数据表明，c-Met/肝细胞生长因子受体是RCC治疗药物的一个有前景的靶点。我们在一个基于医院的大型肾细胞癌系列研究中，检测了MET表达、MET基因拷贝数增加频率和MET基因突变情况，并进行了长期随访。在总共572例肾透明细胞癌中，只有17%的MET表达为阴性，而32%的MET蛋白水平较高。高MET表达和MET拷贝数增加与侵袭性表型和不良患者预后相关。根据靶向二代测序结果，在没有基因扩增的情况下蛋白质水平升高并非由突变所致。我们的数据显示，MET上调的肾透明细胞癌表现出侵袭性行为，在相当比例的高级别癌和转移性疾病患者中，MET拷贝数增加明显。对MET表达和扩增的诊断评估可能对指导肾透明细胞癌患者针对MET信号通路的靶向治疗具有预测价值。
