a Inserm, UMR-1162 , Génomique fonctionnelle des tumeurs solides, IUH , Paris , France.
b Faculté de Médecine , Université Paris Descartes, Sorbonne Paris Cité , Paris , France.
Acta Oncol. 2018 Apr;57(4):498-508. doi: 10.1080/0284186X.2017.1388927. Epub 2017 Nov 2.
Clear-cell renal cell carcinomas (ccRCC) are characterized by hyper-vascularization and can respond to vascular endothelial growth factor receptor (VEGFR) inhibitors such as sunitinib. We aimed to study the predictive value of the expression of genes in the hypoxia induced factor (HIF) - vascular endothelial growth factor (VEGF) - VEGFR-pro-angiogenic pathway in metastatic ccRCC (m-ccRCC) patients treated with sunitinib and the correlation between the expression of these genes and the molecular ccrcc-classification, the expression of genes involved in the immune-suppressive microenvironment and Von Hippel-Lindau (VHL) - and Polybromo-1 (PBRM1) - mutational status.
m-ccRCC patients treated with sunitinib as first-line targeted therapy were included. Gene expression was studied in the primary nephrectomy sample by qRT-PCR, VHL- and PBRM1-mutational status by sequencing. Response rate by RECIST, progression-free survival (PFS) and overall survival (OS) were study endpoints.
One hundred and four patients were included. On multivariate-analysis, HIF2A-, platelet derived growth factor receptor beta (PDGFRB)-, VEGFC-, VEGFR1- and VEGFR2-expression were correlated with PFS and HIF1A-, HIF2A-, VEGFR1- and VEGFR2-expression with OS. VEGFR2-expression showed the strongest association with outcome, being significantly correlated with all outcome parameters. HIF2A, VEGFA, VEGFR1, VEGFR2 and VEGFR3 were highly expressed in the transcriptomic ccrcc2-subtype of tumors, known to be highly sensitive to sunitinib. In the total tumor series, there was no correlation nor inverse correlation between the expression of genes involved in angiogenesis and in the immune-suppressive microenvironment. In tumors with a bi-allelic PBRM1-inactivation, HIF2A-, VEGFA-, VEGFR1- and VEGFR2-expression were higher, compared to tumors with one or two functional PBRM1-alleles.
Intratumoral expression of genes involved in the HIF-VEGF-VEGFR-pro-angiogenic pathway, especially VEGFR2, is associated with favorable outcome on sunitinib in m-ccRCCs. Several genes involved in this pathway are upregulated in the molecular ccrcc2-subgroup, which usually responds well to sunitinib.
透明细胞肾细胞癌（ccRCC）的特点是高度血管化，并且可以对血管内皮生长因子受体（VEGFR）抑制剂（如舒尼替尼）产生反应。我们旨在研究缺氧诱导因子（HIF）-血管内皮生长因子（VEGF）-VEGFR 促血管生成通路中基因表达在接受舒尼替尼治疗的转移性 ccRCC（m-ccRCC）患者中的预测价值，以及这些基因的表达与分子 ccRCC 分类、参与免疫抑制微环境的基因表达以及 Von Hippel-Lindau（VHL）-和 Poly-bromo-1（PBRM1）-突变状态之间的相关性。
纳入接受舒尼替尼作为一线靶向治疗的 m-ccRCC 患者。通过 qRT-PCR 研究原发性肾切除术标本中的基因表达，通过测序研究 VHL-和 PBRM1-突变状态。通过 RECIST 评估反应率、无进展生存期（PFS）和总生存期（OS）是研究终点。
共纳入 104 例患者。多变量分析显示，HIF2A、血小板衍生生长因子受体β（PDGFRB）、VEGFC、VEGFR1 和 VEGFR2 表达与 PFS 相关，HIF1A、HIF2A、VEGFR1 和 VEGFR2 表达与 OS 相关。VEGFR2 表达与结局的相关性最强，与所有结局参数均显著相关。在转录组 ccRCC2 亚类的肿瘤中，HIF2A、VEGFA、VEGFR1、VEGFR2 和 VEGFR3 表达较高，已知对舒尼替尼高度敏感。在整个肿瘤系列中，血管生成和免疫抑制微环境中基因的表达之间既没有相关性也没有反相关性。在具有双等位基因 PBRM1 失活的肿瘤中，与具有一个或两个功能 PBRM1 等位基因的肿瘤相比，HIF2A、VEGFA、VEGFR1 和 VEGFR2 的表达更高。
在 m-ccRCC 中，参与 HIF-VEGF-VEGFR 促血管生成通路的基因的肿瘤内表达，特别是 VEGFR2，与舒尼替尼的良好预后相关。该通路中的几个基因在分子 ccRCC2 亚组中上调，通常对舒尼替尼反应良好。
