Department of Urology, Institute of Urology, West China Hospital, Sichuan University, No. 37 Guoxue Alley, Wuhou District, Chengdu, Sichuan, China.
Department of Pathology, West China Hospital, Sichuan University, Chengdu, China.
Eur J Med Res. 2024 Jul 20;29(1):378. doi: 10.1186/s40001-024-01939-9.
A substantial proportion of patients with metastatic clear cell renal cell carcinoma (ccRCC) cannot derive benefit from immune checkpoint inhibitor (ICI) plus anti-angiogenic agent combination therapy, making identification of predictive biomarkers an urgent need. The members of pleckstrin homology-like domain family A (PHLDA) play critical roles in multiple cancers, whereas their roles in ccRCC remain unknown.
Transcriptomic, clinical, genetic alteration and DNA methylation data were obtained for integrated analyses from TCGA database. RNA sequencing was performed on 117 primary tumors and 79 normal kidney tissues from our center. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis were performed to explore transcriptomic features. Data from three randomized controlled trials (RCT), including CheckMate025, IMmotion151, JAVELIN101, were obtained for validation.
Members of PHLDA family were dysregulated in pan-cancer. Elevated PHLDA2 expression was associated with adverse clinicopathologic parameters and worse prognosis in ccRCC. Aberrant DNA hypomethylation contributed to up-regulation of PHLDA2. An immunosuppressive microenvironment featured by high infiltrates of Tregs and cancer-associated fibroblasts, was observed in ccRCC with higher PHLDA2 expression. Utilizing data from three RCTs, the association of elevated PHLDA2 expression with poor therapeutic efficacy of ICI plus anti-angiogenic combination therapy was confirmed.
Our study revealed that elevated PHLDA2 expression regulated by DNA hypomethylation was correlated with poor prognosis and immunosuppressive microenvironment, and highlighted the role of PHLDA2 as a robust biomarker for predicting therapeutic efficacy of ICI plus anti-angiogenic agent combination therapy in ccRCC, which expand the dimension of precision medicine.
相当一部分转移性透明细胞肾细胞癌（ccRCC）患者无法从免疫检查点抑制剂（ICI）联合抗血管生成药物治疗中获益，因此迫切需要寻找预测生物标志物。PHLDA 家族成员在多种癌症中发挥着关键作用，但其在 ccRCC 中的作用尚不清楚。
从 TCGA 数据库中获取转录组、临床、遗传改变和 DNA 甲基化数据进行综合分析。对 117 例原发肿瘤和 79 例本中心正常肾组织进行 RNA 测序。进行基因本体论和京都基因与基因组百科全书分析、基因集富集分析，以探讨转录组特征。从三个随机对照试验（RCT）中获取数据，包括 CheckMate025、IMmotion151、JAVELIN101，进行验证。
PHLDA 家族成员在泛癌中失调。PHLDA2 表达升高与 ccRCC 的不良临床病理参数和预后不良相关。异常的 DNA 低甲基化导致 PHLDA2 的上调。在 PHLDA2 表达较高的 ccRCC 中，观察到具有高浸润性 Tregs 和癌相关成纤维细胞的免疫抑制微环境。利用三个 RCT 的数据，证实了 PHLDA2 表达升高与 ICI 联合抗血管生成药物治疗疗效不佳的相关性。
本研究表明，由 DNA 低甲基化调节的 PHLDA2 表达升高与不良预后和免疫抑制微环境相关，并强调了 PHLDA2 作为预测 ccRCC 中 ICI 联合抗血管生成药物治疗疗效的强有力生物标志物的作用，扩展了精准医学的维度。
