Department of Urology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
Front Immunol. 2022 Jul 26;13:931906. doi: 10.3389/fimmu.2022.931906. eCollection 2022.
Bladder cancer (BC) threatens the health of human beings worldwide because of its high recurrence rate and mortality. As an actionable biomarker, fibroblast growth factor receptor 3 () alterations have been revealed as a vital biomarker and associated with favorable outcomes in BC. However, the comprehensive relationship between the alteration associated gene expression profile and the prognosis of BC remains ambiguous.
Genomic alteration profile, gene expression data, and related clinical information of BC patients were downloaded from The Cancer Genomics database (TCGA), as a training cohort. Subsequently, the Weighted Gene Co-expression Network Analysis (WGCNA) was conducted to identify the hub modules correlated with alteration. The univariate, multivariate, and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to obtain an alteration-related gene (FARG) prognostic signature and FARG-based nomogram. The receiver operating characteristic (ROC) curve analysis was used for evaluation of the ability of prognosis prediction. The FARG signature was validated in four independent datasets, namely, GSE13507, GSE31684, GSE32548, and GSE48075, from Gene Expression Omnibus (GEO). Then, clinical feature association analysis, functional enrichment, genomic alteration enrichment, and tumor environment analysis were conducted to reveal differential clinical and molecular characterizations in different risk groups. Lastly, the treatment response was evaluated in the immunotherapy-related dataset of the IMvigor210 cohort and the frontline chemotherapy dataset of GSE48276, and the chemo-drug sensitivity was estimated Genomics of Drug Sensitivity in Cancer (GDSC).
There were a total of eleven genes (, , , , , , , , , , and ) identified in the FARG signature, which divided BC patients from the TCGA cohort into high- and low-risk groups. The Kaplan-Meier curve analysis demonstrated that BC patients in the low-risk group have superior overall survival (OS) than those in the high-risk group (median OS: 27.06 months . 104.65 months, < 0.0001). Moreover, the FARG signature not only showed a good performance in prognosis prediction, but also could distinguish patients with different neoplasm disease stages, notably whether patients presented with muscle invasive phenotype. Compared to clinicopathological features, the FARG signature was found to be the only independent prognostic factor, and subsequently, a FARG-based prognostic nomogram was constructed with better ability of prognosis prediction, indicated by area under ROC curve (AUC) values for 1-, 3-, and 5-year OS of 0.69, 0.71, and 0.79, respectively. Underlying the FARG signature, multiple kinds of metabolism- and immune-related signaling pathways were enriched. Genomic alteration enrichment further identified that alterations, especially c.746C>G (p.Ser249Cys), were more prevalent in the low-risk group. Additionally, FARG score was positively correlated with ESTIMATE and TIDE scores, and the low-risk group had abundant enrichment of plasma B cells, CD8+ T cells, CD4+ naive T cells, and helper follicular T cells, implying that patients in the low-risk group were likely to make significant responses to immunotherapy, which was further supported by the analysis in the IMvigor210 cohort as there was a significantly higher response rate among patients with lower FARG scores. The analysis of the GDSC database finally demonstrated that low-risk samples were more sensitive to methotrexate and tipifarnib, whereas those in the high-risk group had higher sensitivities in cisplatin, docetaxel, and paclitaxel, instead.
The novel established FARG signature based on a comprehensive alteration-related transcriptomic profile performed well in prognosis prediction and was also correlated with immunotherapy and chemotherapy treatment responses, which had great potential in future clinical applications.
膀胱癌（BC）因其高复发率和死亡率而威胁着全球人类的健康。作为一种可操作的生物标志物，成纤维细胞生长因子受体 3 () 改变已被揭示为重要的生物标志物，并与 BC 的良好预后相关。然而，与 BC 相关的基因表达谱的综合关系和预后仍然不清楚。
从癌症基因组图谱（TCGA）下载膀胱癌患者的基因组改变谱、基因表达数据和相关临床信息作为训练队列。随后，进行加权基因共表达网络分析（WGCNA）以鉴定与 改变相关的枢纽模块。使用单变量、多变量和最小绝对收缩和选择算子（LASSO）Cox 回归分析获得与 改变相关的基因（FARG）预后特征和基于 FARG 的列线图。使用接收者操作特征（ROC）曲线分析评估预后预测能力。在来自基因表达综合数据库（GEO）的四个独立数据集 GSE13507、GSE31684、GSE32548 和 GSE48075 中验证了 FARG 特征。然后，进行临床特征关联分析、功能富集、基因组改变富集和肿瘤环境分析，以揭示不同风险组的差异临床和分子特征。最后，在 IMvigor210 队列的免疫治疗相关数据集和 GSE48276 的一线化疗数据集中评估治疗反应，并使用癌症基因组药物敏感性（GDSC）估计化疗药物敏感性。
在 FARG 特征中确定了 11 个基因（、、、、、、、、、和），这些基因将 TCGA 队列中的膀胱癌患者分为高风险和低风险组。Kaplan-Meier 曲线分析表明，低风险组的 BC 患者的总生存期（OS）优于高风险组（中位 OS：27.06 个月 vs 104.65 个月，<0.0001）。此外，FARG 特征不仅在预后预测方面表现良好，而且能够区分不同肿瘤疾病阶段的患者，特别是是否存在肌层浸润表型的患者。与临床病理特征相比，FARG 特征是唯一的独立预后因素，随后构建了基于 FARG 的预后列线图，其 1、3 和 5 年 OS 的 AUC 值分别为 0.69、0.71 和 0.79，具有更好的预后预测能力。在 FARG 特征的基础上，富集了多种代谢和免疫相关信号通路。基因组改变富集进一步鉴定出 改变，特别是 c.746C>G（p.Ser249Cys），在低风险组中更为常见。此外，FARG 评分与 ESTIMATE 和 TIDE 评分呈正相关，低风险组富含血浆 B 细胞、CD8+T 细胞、CD4+幼稚 T 细胞和辅助滤泡 T 细胞，这表明低风险组的患者可能对免疫治疗有明显的反应，这在 IMvigor210 队列中的分析中得到了进一步支持，因为在低风险组中患者的反应率显著更高。最后对 GDSC 数据库的分析表明，低风险样本对甲氨蝶呤和替匹法尼更敏感，而高风险组对顺铂、多西他赛和紫杉醇的敏感性更高。
基于全面的 改变相关转录组谱建立的新的 FARG 特征在预后预测方面表现良好，并且与免疫治疗和化疗反应相关，在未来的临床应用中有很大的潜力。
