A cell of origin gene signature indicates human bladder cancer has distinct cellular progenitors.
A cell of origin gene signature indicates human bladder cancer has distinct cellular progenitors.
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原始基因特征的细胞表明人膀胱癌具有不同的细胞祖细胞。
DOI：
10.1002/stem.1625
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发表时间：
2014-04
期刊：
影响因子：
5.2
通讯作者：
Theodorescu, Dan
中科院分区：
文献类型：
--
作者：
Dancik, Garrett M.;Owens, Charles R.;Iczkowski, Kenneth A.;Theodorescu, Dan
有两种不同形式的尿路上皮（膀胱）癌：肌肉浸润性（MI）和非肌肉浸润性（NMI）疾病。由于目前认为膀胱癌是通过基底层的尿路上皮细胞的转化而产生的，因此已经基于在此类细胞中发现的表达标志物分离了膀胱癌干细胞（CSC）。然而，这些CSC仅在MI肿瘤中鉴定，提出了NMI肿瘤祖细胞不产生于基底室的有趣假设。为了验证这一假设，我们对激光捕获显微切割的基底细胞和伞细胞进行了全基因组表达谱分析，这是正常尿路上皮中两种组织学上最不同的细胞类型，并开发了区分这些细胞的细胞起源（COO）基因签名。在多个患者队列中，COO特征是比其他膀胱、通用或乳腺CSC特征和膀胱细胞分化标志物更好的分期和生存预测因子。为了评估NMI和MI肿瘤是否来自不同的（DPC）或共同的（CPC）祖细胞，我们开发了一种新的统计框架，该框架预测COO评分作为驱动MI或NMI膀胱癌的已知遗传改变（TP53，HRAS，KDM6A和FGFR3）的函数，并将其与观察到的肿瘤COO评分进行比较。对5个队列中的874例患者进行分析，确定DPC模型是现有数据的最佳拟合。这一观察结果支持NMI和MI肿瘤中不同的祖细胞，并为我们对膀胱癌生物学的理解提供了范式转变，这具有重要的诊断和治疗意义。
There are two distinct forms of urothelial (bladder) cancer: muscle-invasive (MI) and non-muscle invasive (NMI) disease. Since it is currently believed that bladder cancer arises by transformation of urothelial cells of the basal layer, bladder cancer stem cells (CSCs) have been isolated based on expression markers found in such cells. However, these CSCs have only been identified in MI tumors raising the intriguing hypothesis that NMI tumor progenitors do not arise from the basal compartment. To test this hypothesis, we carried out genomewide expression profiling of laser capture microdissected basal and umbrella cells, the two most histologically distinct cell types in normal urothelium and developed a Cell Of Origin (COO) gene signature that distinguishes these. The COO signature was a better predictor of stage and survival than other bladder, generic or breast CSC signatures and bladder cell differentiation markers in multiple patient cohorts. To assess whether NMI and MI tumors arise from a distinct (DPC) or common (CPC) progenitor cell, we developed a novel statistical framework that predicts COO score as a function of known genetic alterations (TP53, HRAS, KDM6Aand FGFR3) that drive either MI or NMI bladder cancer and compared this to the observed COO score of the tumor. Analysis of 874 patients in 5 cohorts established the DPC model as the best fit to the available data. This observation supports distinct progenitor cells in NMI and MI tumors and provides a paradigm shift in our understanding of bladder cancer biology that has significant diagnostic and therapeutic implications.
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从微阵列时程数据中提取二进制信号。
影响因子：
14.9
作者：
Sahoo D;Dill DL;Tibshirani R;Plevritis SK
通讯作者：
Plevritis SK
DOI：
10.1073/pnas.0906549106
发表时间：
2009-08-18
影响因子：
11.1
作者：
Chan, Keith Syson;Espinosa, Inigo;Weissman, Irving L.
通讯作者：
Weissman, Irving L.
影响因子：
44.1
作者：
Jiang, Wei;Wang, Jinzhao;Zhang, Yi
通讯作者：
Zhang, Yi
影响因子：
64.8
作者：
Park, In-Hyun;Zhao, Rui;Daley, George Q.
通讯作者：
Daley, George Q.
影响因子：
3.7
作者：
Choi W;Shah JB;Tran M;Svatek R;Marquis L;Lee IL;Yu D;Adam L;Wen S;Shen Y;Dinney C;McConkey DJ;Siefker-Radtke A
通讯作者：
Siefker-Radtke A