Brada Muriel D, Karakulak Tülay, Schraml Peter, Haberecker Martina, Rutishauser Dorothea, Ross Jeffrey S, Eberli Daniel, Moch Holger
Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
Department of Molecular Life Sciences, University of Zurich, Zurich, Switzerland.
J Pathol Clin Res. 2025 May;11(3):e70028. doi: 10.1002/2056-4538.70028.
Novel treatment options for metastatic renal cell carcinomas (RCC) include specific MET inhibitors, GAS6/AXL inhibitors, and SRC inhibitors. The interplay between c-MET, SRC, AXL expression, and their gene mutation patterns in different renal carcinoma subtypes is unclear. To improve the understanding of these signaling pathways, we analyzed c-MET, AXL, and SRC expression in 590 clear cell RCC (ccRCC) and 127 papillary RCC (pRCC) by immunohistochemistry and integrated sequencing data to investigate the frequency of MET, AXL, and SRC gene mutations, their expression levels, and the presence of splice variants. In TCGA and in Foundation Medicine, Inc. (FMI) datasets, AXL and SRC gene alterations were extremely rare (<2%) or absent in ccRCC (n = 531 and 2,781, respectively) and pRCC (n = 290 and 566, respectively). On the other hand, MET mutations or amplifications were found in 9.7% (TCGA) and 10.2% (FMI) of pRCC. We show that strong SRC staining intensity by immunohistochemistry is associated with high tumor stage, high grade, and shorter survival in ccRCC (p < 0.001 each). AXL expression correlates with high stage and grade in ccRCC (p < 0.001 each). Both SRC and AXL expression were independent prognostic parameters in multivariate analysis (p < 0.05). MET expression is associated with longer survival in pRCC (p < 0.05). Our TCGA data analysis aligns with SRC immunohistochemistry findings on tumor stage and shorter survival in ccRCC. TCGA expression data showed a moderate positive correlation between AXL and c-MET in pRCC. In addition, we identified alternative splicing events reported for AXL in pRCC, and MET and SRC in ccRCC, across various alternative splicing databases. In conclusion, we identified high SRC expression as a biomarker for poor prognosis of ccRCC. Our data demonstrate c-MET, AXL, and SRC signaling pathway interactions independent of c-MET, AXL, and SRC mutations in ccRCC.
转移性肾细胞癌（RCC）的新型治疗选择包括特异性MET抑制剂、GAS6/AXL抑制剂和SRC抑制剂。c-MET、SRC、AXL表达及其基因突变模式在不同肾癌亚型中的相互作用尚不清楚。为了更好地理解这些信号通路，我们通过免疫组织化学分析了590例透明细胞肾细胞癌（ccRCC）和127例乳头状肾细胞癌（pRCC）中c-MET、AXL和SRC的表达，并整合测序数据以研究MET、AXL和SRC基因突变的频率、它们的表达水平以及剪接变体的存在情况。在TCGA数据集和Foundation Medicine公司（FMI）的数据集中，AXL和SRC基因改变在ccRCC（分别为n = 531和2781）和pRCC（分别为n = 290和566）中极其罕见（<2%）或不存在。另一方面，在9.7%（TCGA）和10.2%（FMI）的pRCC中发现了MET突变或扩增。我们发现，免疫组织化学显示SRC染色强度高与ccRCC的高肿瘤分期、高分级和较短生存期相关（每项p < 0.001）。AXL表达与ccRCC的高分期和高分级相关（每项p < 0.001）。在多变量分析中，SRC和AXL表达均为独立的预后参数（p < 0.05）。MET表达与pRCC的较长生存期相关（p < 0.05）。我们对TCGA数据分析与SRC免疫组织化学关于ccRCC肿瘤分期和较短生存期的结果一致。TCGA表达数据显示pRCC中AXL和c-MET之间存在中度正相关。此外，我们在多个可变剪接数据库中确定了pRCC中AXL以及ccRCC中MET和SRC报道的可变剪接事件。总之，我们确定高SRC表达是ccRCC预后不良的生物标志物。我们的数据证明了ccRCC中c-MET、AXL和SRC信号通路的相互作用独立于c-MET、AXL和SRC突变。
