Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, 100101, China.
Cell Oncol (Dordr). 2022 Aug;45(4):677-687. doi: 10.1007/s13402-022-00691-8. Epub 2022 Jul 14.
Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) are being used for the first-line treatment of metastatic clear cell renal cell carcinoma (mccRCC). Here, we set out to explore associations between genomic statuses, gene expression clusters and clinical outcomes of mccRCCs upon the application of VEGFR-TKIs.
A retrospective study of 56 patients with mccRCC who received first-line VEGFR-TKIs and who underwent genomic profiling and whole transcriptome sequencing was conducted. Survival analysis was carried out using log-rank tests and Cox regression analyses, and Kaplan-Meier curves were plotted. Clustering was performed using the K-means method.
Among the 56 patients tested, 17 harbored DNA Damage and Repair (DDR) pathway alterations and 35 VHL mutations. The median progression-free survival (PFS) rates for the DDR and VHL alteration groups were 18 and 18 months, respectively, compared with 14 and 10 months for the nonmutant groups. DDR mutations, VHL mutations and co-mutations were identified as prognostic biomarkers of a longer PFS (p = 0.017, 0.04, 0.014). K-means clustering of expressed transcripts revealed three clusters of 40 patients: C_1, C_2 and C_3. The C_1 cluster exhibited the best PFS and objective response rate (ORR) to TKI therapy, with the highest proportion of DDR and VHL mutations. Further analysis of the tumor immune environment revealed that the C_1 cluster was enriched in activated CD8 T cells and effector CD4 T cells, whereas the C_2 cluster was enriched in eosinophils, mast cells and DC cells and, thus, in immunosuppressive cells.
We found that patients with mccRCC harboring DDR and VHL alterations were more likely to benefit from first-line VEGF-TKI systemic therapy than patients with wild-type disease. In addition, we found that a three-cluster prognostic model based on gene expression can predict PFS and ORR, which was well-matched with activated TIL infiltration.
血管内皮生长因子受体酪氨酸激酶抑制剂（VEGFR-TKIs）被用于治疗转移性透明细胞肾细胞癌（mccRCC）的一线治疗。在这里，我们旨在探索在应用 VEGFR-TKIs 时，mccRCC 的基因组状态、基因表达簇与临床结果之间的关联。
对 56 例接受一线 VEGFR-TKIs 治疗并进行基因组分析和全转录组测序的 mccRCC 患者进行回顾性研究。使用对数秩检验和 Cox 回归分析进行生存分析，并绘制 Kaplan-Meier 曲线。使用 K-means 方法进行聚类。
在 56 例检测患者中，17 例存在 DNA 损伤和修复（DDR）途径改变，35 例存在 VHL 突变。DDR 改变组和 VHL 突变组的中位无进展生存期（PFS）分别为 18 和 18 个月，而非突变组分别为 14 和 10 个月。DDR 突变、VHL 突变和共突变被确定为更长 PFS 的预后生物标志物（p=0.017、0.04、0.014）。表达转录本的 K-means 聚类显示 40 例患者的三个聚类：C_1、C_2 和 C_3。C_1 聚类表现出最佳的 PFS 和 TKI 治疗的客观缓解率（ORR），具有最高比例的 DDR 和 VHL 突变。对肿瘤免疫环境的进一步分析表明，C_1 聚类富含激活的 CD8 T 细胞和效应 CD4 T 细胞，而 C_2 聚类富含嗜酸性粒细胞、肥大细胞和 DC 细胞，因此富含免疫抑制细胞。
我们发现，mccRCC 患者携带 DDR 和 VHL 改变比野生型疾病患者更有可能从一线 VEGF-TKI 系统治疗中获益。此外，我们发现，基于基因表达的三聚类预后模型可以预测 PFS 和 ORR，这与激活的 TIL 浸润非常吻合。
