Zhao Junsong, Siegmund Kimberly D, Shibata Darryl, Marjoram Paul
Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA.
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
J Theor Biol. 2014 Oct 21;359:136-45. doi: 10.1016/j.jtbi.2014.05.027. Epub 2014 Jun 5.
A tumor is thought to start from a single cell and genome. Yet genomes in the final tumor are typically heterogeneous. The mystery of this intratumoral heterogeneity (ITH) has not yet been uncovered, but much of this ITH may be secondary to replication errors. Methylation of cytosine bases often exhibits ITH and therefore may encode the ancestry of the tumor. In this study, we measure the passenger methylation patterns of a specific CpG region in 9 colorectal tumors by bisulfite sequencing and apply a tumor development model. Based on our model, we are able to retrieve information regarding the ancestry of each tumor using approximate Bayesian computation. With a large simulation study we explore the conditions under which we can estimate the model parameters, and the initial state of the first transformed cell. Finally we apply our analysis to clinical data to gain insight into the dynamics of tumor formation.
肿瘤被认为起源于单个细胞和基因组。然而，最终肿瘤中的基因组通常是异质性的。这种肿瘤内异质性（ITH）的奥秘尚未被揭开，但这种ITH的很大一部分可能是复制错误的结果。胞嘧啶碱基的甲基化常常表现出ITH，因此可能编码肿瘤的谱系。在本研究中，我们通过亚硫酸氢盐测序测量了9个结肠直肠癌肿瘤中特定CpG区域的过客甲基化模式，并应用了肿瘤发展模型。基于我们的模型，我们能够使用近似贝叶斯计算检索每个肿瘤谱系的信息。通过一项大型模拟研究，我们探索了能够估计模型参数以及第一个转化细胞初始状态的条件。最后，我们将分析应用于临床数据，以深入了解肿瘤形成的动态过程。
