Prognostic Power of a Tumor Differentiation Gene Signature for Bladder Urothelial Carcinomas
Prognostic Power of a Tumor Differentiation Gene Signature for Bladder Urothelial Carcinomas
复制标题
DOI：
10.1093/jnci/djx243
复制
发表时间：
2018-05-01
影响因子：
10.3
通讯作者：
Chan, Keith Syson
中科院分区：
文献类型：
--
作者：
Mo, Qianxing;Nikolos, Fotis;Chan, Keith Syson
背景：肌层浸润性膀胱癌 (MIBC) 每年导致全球约 150 000 例死亡 MIBC 患者的生存情况存在异质性，没有经过临床验证的分子标志物可预测临床结果 非 MIBC (NMIBC) 通常具有良好的结果，但部分进展为 MIBC 因此，开发可指导决策的预后工具对于改善膀胱尿路上皮癌的临床管理至关重要。 方法：肿瘤分级由病理学定义评估肿瘤细胞分化，并且通常与临床结果相关 目前的研究推断了这一传统观点，并将其与分子分析相结合 我们开发了一种 18 基因特征，从分子上定义尿路上皮细胞分化，从而将 MIBC 和 NMIBC 分为基础和分化两个亚组 我们评估了这种“肿瘤分化特征”和其他三个现有基因特征的预后能力，包括癌症基因组图谱（TCGA；2707 个基因），MD 安德森癌症中心（MDA，2252 个基因/2697 个探针）和北卡罗来纳大学教堂山分校（UNC，47 个基因）使用源自 MIBC 和 NMIBC 患者的 5 个基因表达数据集。所有统计检验均为双面。 结果：肿瘤分化特征证明了将 MIBC 患者分层为不同总体生存结果的一致性和统计稳健性（TCGA 队列 1，P = .03；MDA 发现，P = .009；MDA 验证，P = .01)，而其他特征则不一致 此外，我们分析了 NMIBC 的进展（Ta/T1 进展至 >= T2）概率 NMIBC 患者具有与较差进展结果相关的基础肿瘤分化特征 (P = .008) 基因功能术语富集和基因集富集分析显示，涉及免疫反应和炎症反应的生物过程的基因是基底膀胱癌中升高程度最高的基因之一，这表明它们是免疫检查点的候选者结论：这些结果提供了明确的证据，表明生物学优先的聚类方法可以对患者分层产生有意义的见解，并揭示影响未来治疗方法的可靶向分子途径。
Background: Muscle-invasive bladder cancers (MIBCs) cause approximately 150 000 deaths per year worldwide Survival for MIBC patients is heterogeneous, with no clinically validated molecular markers that predict clinical outcome Non-MIBCs (NMIBCs) generally have favorable outcome, however, a portion progress to MIBC Hence, development of a prognostic tool that can guide decision-making is crucial for improving clinical management of bladder urothelial carcinomas.Methods: Tumor grade is defined by pathologic evaluation of tumor cell differentiation, and it often associates with clinical outcome The current study extrapolates this conventional wisdom and combines it with molecular profiling We developed an 18-gene signature that molecularly defines urothelial cellular differentiation, thus classifying MIBCs and NMIBCs into two subgroups basal and differentiated We evaluated the prognostic capability of this "tumor differentiation signature" and three other existing gene signatures including the The Cancer Genome Atlas (TCGA; 2707 genes), MD Anderson Cancer Center (MDA, 2252 genes/2697 probes), and University of North Carolina at Chapel Hill (UNC, 47 genes) using five gene expression data sets derived from MIBC and NMIBC patients All statistical tests were two-sided.Results: The tumor differentiation signature demonstrated consistency and statistical robustness toward stratifying MIBC patients into different overall survival outcomes (TCGA cohort 1, P = .03; MDA discovery, P = .009; MDA validation, P = .01), while the other signatures were not as consistent In addition, we analyzed the progression (Ta/Tl progressing to >= T2) probability of NMIBCs NMIBC patients with a basal tumor differentiation signature associated with worse progression outcome (P = .008) Gene functional term enrichment and gene set enrichment analyses revealed that genes involved m the biologic process of immune response and inflammatory response are among the most elevated within basal bladder cancers, implicating them as candidates for immune checkpoint therapiesConclusions: These results provide definitive evidence that a biology-prioritizing clustering methodology generates meaningful insights into patient stratification and reveals targetable molecular pathways to impact future therapeutic approach.