Three differentiation states risk-stratify bladder cancer into distinct subtypes
Three differentiation states risk-stratify bladder cancer into distinct subtypes
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DOI：
10.1073/pnas.1120605109
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发表时间：
2012-02-07
影响因子：
11.1
通讯作者：
Chan, Keith S.
中科院分区：
文献类型：
--
作者：
Volkmer, Jens-Peter;Sahoo, Debashis;Chan, Keith S.
目前膀胱癌的临床判断主要依赖于病理分期和分级。我们研究了基于发育生物学方法的肿瘤细胞分化的分子分类是否可以提供额外的预后信息。利用大量预先存在的基因表达数据库，我们开发了一个生物监督计算模型来预测与BC分化相对应的标记。为了提供机制的见解，我们通过异种移植评估了相对的致瘤性和分化潜力。然后，我们将鉴定的标记物的预后效用与基因表达和福尔马林固定石蜡包埋（FFPE）组织数据集中的结果联系起来。我们的数据表明，根据其分化状态，BC可以被细分为三个亚型：基础型、中间型和分化型，其中每个亚型中只有最原始的肿瘤细胞亚群能够产生异种移植肿瘤并概括下游群体。我们发现角蛋白14 （KRT14）标志着KRT5和KRT20表达之前最原始的分化状态。此外，在单因素和多因素分析中，KRT14表达始终与较差的预后相关。我们在此根据其分化状态确定了三种不同的BC亚型，每种亚型都有独特的肿瘤起始群体。
Current clinical judgment in bladder cancer (BC) relies primarily on pathological stage and grade. We investigated whether a molecular classification of tumor cell differentiation, based on a developmental biology approach, can provide additional prognostic information. Exploiting large preexisting gene-expression databases, we developed a biologically supervised computational model to predict markers that correspond with BC differentiation. To provide mechanistic insight, we assessed relative tumorigenicity and differentiation potential via xenotransplantation. We then correlated the prognostic utility of the identified markers to outcomes within gene expression and formalin-fixed paraffin-embedded (FFPE) tissue datasets. Our data indicate that BC can be subclassified into three subtypes, on the basis of their differentiation states: basal, intermediate, and differentiated, where only the most primitive tumor cell subpopulation within each subtype is capable of generating xenograft tumors and recapitulating downstream populations. We found that keratin 14 (KRT14) marks the most primitive differentiation state that precedes KRT5 and KRT20 expression. Furthermore, KRT14 expression is consistently associated with worse prognosis in both univariate and multivariate analyses. We identify here three distinct BC subtypes on the basis of their differentiation states, each harboring a unique tumor-initiating population.