FISHtrees 3.0: Tumor Phylogenetics Using a Ploidy Probe.
FISHtrees 3.0: Tumor Phylogenetics Using a Ploidy Probe.
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FISHtrees 3.0：使用倍性探针进行肿瘤系统发育。
DOI：
10.1371/journal.pone.0158569
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Schäffer AA
中科院分区：
文献类型：
--
作者：
Gertz EM;Chowdhury SA;Lee WJ;Wangsa D;Heselmeyer-Haddad K;Ried T;Schwartz R;Schäffer AA
荧光原位杂交（FISH）技术的发展使得检测数百个实体瘤细胞中的多拷贝数变化成为可能。使用FISH、测序和其他技术的研究已经揭示了大量的肿瘤内异质性。肿瘤中亚克隆的进化可以通过同源性来模拟。肿瘤通常含有非整倍体或多倍体细胞群。使用FISH探针来估计倍性的变化可以指导创建对倍性变化和个体基因拷贝数变化进行建模的树。我们提出了FISHtrees 3.0，它实现了基于混合整数线性规划（MILP）的基于倍性的树构建方法。FISH树中基于倍性的建模包括将单个基因变化的树合并成多个基因和倍性变化的树的问题的新公式。当从每个患者收集多个样品时，随着时间或肿瘤区域而变化，评估样品之间肿瘤进展的相似性是有用的。因此，我们进一步在FISHTrees 3.0中实现了一种新的方法来构建多个样本的共识图。我们验证了FISH树3.0的模拟数据和FISH数据配对的情况下，颈部原发性和转移性肿瘤和配对乳腺导管原位癌（DCIS）和浸润性导管癌（IDC）。对模拟数据的测试表明，相对于先前的无倍性方法，基于倍性的方法提高了准确性。对真实的数据的测试进一步证明了这些方法对肿瘤进展过程的新颖见解。DCIS样本的树比配对IDC样本的树复杂得多。共识图显示两组大多数配对样本之间存在实质性分歧。DCIS和IDC树之间的低共识可能有助于解释难以找到预测哪些DCIS病例进展为IDC的风险最大的生物标志物。FISHTrees软件可在ftp://ftp.ncbi.nih.gov/pub/FISHtrees上获得。
Advances in fluorescence in situ hybridization (FISH) make it feasible to detect multiple copy-number changes in hundreds of cells of solid tumors. Studies using FISH, sequencing, and other technologies have revealed substantial intra-tumor heterogeneity. The evolution of subclones in tumors may be modeled by phylogenies. Tumors often harbor aneuploid or polyploid cell populations. Using a FISH probe to estimate changes in ploidy can guide the creation of trees that model changes in ploidy and individual gene copy-number variations. We present FISHtrees 3.0, which implements a ploidy-based tree building method based on mixed integer linear programming (MILP). The ploidy-based modeling in FISHtrees includes a new formulation of the problem of merging trees for changes of a single gene into trees modeling changes in multiple genes and the ploidy. When multiple samples are collected from each patient, varying over time or tumor regions, it is useful to evaluate similarities in tumor progression among the samples. Therefore, we further implemented in FISHtrees 3.0 a new method to build consensus graphs for multiple samples. We validate FISHtrees 3.0 on a simulated data and on FISH data from paired cases of cervical primary and metastatic tumors and on paired breast ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC). Tests on simulated data show improved accuracy of the ploidy-based approach relative to prior ploidyless methods. Tests on real data further demonstrate novel insights these methods offer into tumor progression processes. Trees for DCIS samples are significantly less complex than trees for paired IDC samples. Consensus graphs show substantial divergence among most paired samples from both sets. Low consensus between DCIS and IDC trees may help explain the difficulty in finding biomarkers that predict which DCIS cases are at most risk to progress to IDC. The FISHtrees software is available at ftp://ftp.ncbi.nih.gov/pub/FISHtrees.