Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes.

中文翻译：

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膀胱尿路上皮癌中受体酪氨酸激酶的自分泌信号

膀胱癌（BCa）的全面表征已建立具有明显改变和生存趋势的分子表型类别。将这些研究扩展到酪氨酸激酶（TK）家族中来确定疾病的驱动因素，可能会改善我们使用TK抑制剂治疗特定患者群体或个人的使用。我们在癌症基因组图谱（TCGA）肌肉浸润性BCa数据集（n> 400）中检查了TKs的表达分布类别（n = 89）。潜在致癌性改变（过度表达和/或扩增）的患者资料将传统知识归为三类；与没有改变的患者相比，第1和第3组传统知识的改变与患者生存率显着降低有关。许多传统知识途径诱导上皮-间质转化（EMT），从而促进肿瘤的侵袭和转移。在9种EMT转录激活因子中，过表达和/或扩增发生在43％的TCGA患者中。TK和EMT转录激活因子的共现改变涉及大多数第1组TK。这些事件中有24％与患者生存率显着降低有关。在16％的TCGA病例和几种BCa衍生的细胞系中，受体TK及其同源配体同时发生改变。在BCa细胞系中GAS6，MST1或CSF1或它们各自的受体（AXL，MST1R和CSF1R）的抑制与受体激活，细胞迁移，细胞增殖和锚定无关细胞生长降低有关。这些研究揭示了BCa中潜在致癌的TK途径相关改变的模式和患病率，并确定了与BCa患者生存率降低相关的特定改变。