A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis
A Modeling Approach to Explain Mutually Exclusive and Co-Occurring Genetic Alterations in Bladder Tumorigenesis
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DOI：
10.1158/0008-5472.can-15-0602
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发表时间：
2015-10-01
期刊：
影响因子：
11.2
通讯作者：
Calzone, Laurence
中科院分区：
文献类型：
--
作者：
Remy, Elisabeth;Rebouissou, Sandra;Calzone, Laurence
遗传改变之间的关系，如共同出现或相互排斥，经常在癌症中观察到，在那里他们的理解可能会提供新的见解病因学和临床管理。在这项研究中，我们结合了统计分析和计算建模来解释178例膀胱肿瘤患者（肌肉浸润性或非肌肉浸润性）的遗传改变模式。对频繁改变的基因的统计分析确定了配对关联，包括共同出现或相互排斥。关注参与生长因子受体信号传导、细胞周期和凋亡进入的蛋白编码基因的遗传改变，我们通过文献检索补充了这一分析，重点关注我们数据集的九对遗传改变，随后在其他三个公开的数据集中进行了验证。为了理解这些关联模式的原因和背景，同时考虑相关信号通路的动态，我们建立了一个逻辑模型。该模型首先在已发表的突变小鼠数据上进行了验证，然后用于研究模式并得出反直觉观察的结论，从而可以预测结合遗传改变有利于肿瘤发生的条件。例如，虽然CDKN2A纯合缺失发生在FGFR 3激活突变的背景下，但我们的模型表明，额外的PIK3CA突变或p21CIP缺失将极大地有利于侵袭性。此外，该模型揭示了基因改变的时间顺序，例如，如果FGFR3首先突变，则FGFR3和TP 53突变的互斥性如何解释。总的来说，我们的工作显示了如何通过膀胱癌的两个主要进展途径预测导致侵袭性的主要基因改变的组合。(C)2015年AACR。
Relationships between genetic alterations, such as co-occurrence or mutual exclusivity, are often observed in cancer, where their understanding may provide new insights into etiology and clinical management. In this study, we combined statistical analyses and computational modeling to explain patterns of genetic alterations seen in 178 patients with bladder tumors (either muscle-invasive or non-muscle-invasive). A statistical analysis on frequently altered genes identified pair associations, including co-occurrence or mutual exclusivity. Focusing on genetic alterations of protein-coding genes involved in growth factor receptor signaling, cell cycle, and apoptosis entry, we complemented this analysis with a literature search to focus on nine pairs of genetic alterations of our dataset, with subsequent verification in three other datasets available publicly. To understand the reasons and contexts of these patterns of associations while accounting for the dynamics of associated signaling pathways, we built a logical model. This model was validated first on published mutant mice data, then used to study patterns and to draw conclusions on counter-intuitive observations, allowing one to formulate predictions about conditions where combining genetic alterations benefits tumorigenesis. For example, while CDKN2A homozygous deletions occur in a context of FGFR3-activating mutations, our model suggests that additional PIK3CA mutation or p21CIP deletion would greatly favor invasiveness. Furthermore, the model sheds light on the temporal orders of gene alterations, for example, showing how mutual exclusivity of FGFR3 and TP53 mutations is interpretable if FGFR3 is mutated first. Overall, our work shows how to predict combinations of the major gene alterations leading to invasiveness through two main progression pathways in bladder cancer. (C) 2015 AACR.