缺氧诱导因子通路基因预测转移性透明细胞肾细胞癌的生存。
Hypoxia-inducible factor pathway genes predict survival in metastatic clear cell renal cell carcinoma.
机构信息
Department of Surgery (Urology), Cedars-Sinai Medical Center, Los Angeles, CA.
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA.
出版信息
Urol Oncol. 2022 Nov;40(11):495.e1-495.e10. doi: 10.1016/j.urolonc.2022.07.010. Epub 2022 Aug 13.
PURPOSE
Hypoxia inducible factor (HIF) pathway alterations drive progression of clear cell renal cell carcinoma (ccRCC). We aim to evaluate genes within the canonical and non-canonical HIF pathways as predictors of survival in metastatic ccRCC.
MATERIALS AND METHODS
Gene expression was determined from 324 archival pretreatment nephrectomy specimens from CALGB90206, a phase III trial of patients treated with interferon alpha (INF-α) vs. INF-α plus bevacizumab. TaqMan RT-qPCR was performed using RNA from tumors macrodissected based on review by genitourinary pathology.
RESULTS
A total of 35 HIF-related genes were assessed by Cox regression analysis. After adjusting for sex and Memorial Sloan Kettering Cancer Center risk score (MSKCC-RS), 11 genes predicted OS: HIF2A (HR 1.059, P = 0.012), EGLN3 (HR 1.089, P = 0.012), VEGFC (HR 0.904, P = 0.039), VEGFD (HR 1.085, P = 0.016), FLT4 (HR 1.093, P = 0.038), CCND1 (HR 1.077, P = 0.026), TGFA (HR 1.127, P = 0.003), EGFR (HR 1.151, P = 0.028), VHL (HR 0.764, P = 0.002), HSP90AA1 (HR 0.845, P = 0.002), and PTEN (HR 1.163, P = 0.050); 7 genes predicted PFS: HIF2A (HR 1.060, P = 0.011), CCND1 (HR 1.082, P = 0.016), TGFA (HR 1.096, P = 0.026), EP300 (HR 1.171, P = 0.031), VHL (HR 0.775, P = 0.007), HSP90AA1 (HR 0.871, P = 0.015), and TP53 (HR 1.119, P = 0.050). Most of these genes validated as significant predictors of survival in the external, TCGA dataset. In multivariate analysis of all externally validated genes, VEGFC (HR 0.906, P = 0.043), TGFA (HR 1.122, P = 0.003), CITED2 (HR 1.113, P = 0.035) and EP300 (HR 1.136, P = 0.049) predicted OS; and HIF2A (HR 1.049, P = 0.036) and EP300 (HR 1.199, P = 0.010) predicted PFS. EGLN3 (HR 1.156, P = 0.045) and BNIP3 (HR 1.254, P = 0.049) significantly interacted with treatment status and predicted PFS in patients treated with IFN-α and IFN-α+bevacizumab, respectively.
CONCLUSIONS
We identified specific gene isoforms in both the canonical and non-canonical HIF pathways associated with metastatic RCC survival. EGLN3 and BNIP3 showed significant interaction with treatment arm and may be predictive of treatment response. We have identified genes for future prospective investigation as predictive biomarkers and novel drug targets.
目的
缺氧诱导因子（HIF）通路改变驱动肾透明细胞癌（ccRCC）的进展。我们旨在评估经典和非经典 HIF 通路中的基因作为转移性 ccRCC 患者生存的预测因子。
材料和方法
使用来自 CALGB90206 的 324 份预处理肾切除术标本中的基因表达，这是一项干扰素 α（INF-α）与 INF-α+贝伐单抗治疗患者的 III 期试验。使用基于泌尿生殖病理审查的肿瘤宏观解剖 RNA 进行 TaqMan RT-qPCR。
结果
通过 Cox 回归分析评估了 35 个与 HIF 相关的基因。在校正性别和纪念斯隆凯特琳癌症中心风险评分（MSKCC-RS）后，11 个基因预测 OS：HIF2A（HR 1.059，P=0.012）、EGLN3（HR 1.089，P=0.012）、VEGFC（HR 0.904，P=0.039）、VEGFD（HR 1.085，P=0.016）、FLT4（HR 1.093，P=0.038）、CCND1（HR 1.077，P=0.026）、TGFA（HR 1.127，P=0.003）、EGFR（HR 1.151，P=0.028）、VHL（HR 0.764，P=0.002）、HSP90AA1（HR 0.845，P=0.002）和 PTEN（HR 1.163，P=0.050）；7 个基因预测 PFS：HIF2A（HR 1.060，P=0.011）、CCND1（HR 1.082，P=0.016）、TGFA（HR 1.096，P=0.026）、EP300（HR 1.171，P=0.031）、VHL（HR 0.775，P=0.007）、HSP90AA1（HR 0.871，P=0.015）和 TP53（HR 1.119，P=0.050）。这些基因中的大多数在外部的 TCGA 数据集作为生存的显著预测因子得到验证。在所有外部验证基因的多变量分析中，VEGFC（HR 0.906，P=0.043）、TGFA（HR 1.122，P=0.003）、CITED2（HR 1.113，P=0.035）和 EP300（HR 1.136，P=0.049）预测 OS；HIF2A（HR 1.049，P=0.036）和 EP300（HR 1.199，P=0.010）预测 PFS。EGLN3（HR 1.156，P=0.045）和 BNIP3（HR 1.254，P=0.049）与治疗状态显著相互作用，分别预测接受 IFN-α和 IFN-α+贝伐单抗治疗的患者的 PFS。
结论
我们确定了与转移性 RCC 生存相关的经典和非经典 HIF 通路中的特定基因亚型。EGLN3 和 BNIP3 与治疗臂有显著的相互作用，可能是治疗反应的预测因子。我们已经确定了未来作为预测生物标志物和新药物靶点的候选基因。
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