using dna methylation patterns to infer tumor ancestry使用dna甲基化模式来推断肿瘤血统.pdfVIP

Using DNA Methylation Patterns to Infer Tumor Ancestry 1 1 2 1 You Jin Hong , Paul Marjoram , Darryl Shibata , Kimberly D. Siegmund * 1 Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America, 2 Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America Abstract Background: Exactly how human tumors grow is uncertain because serial observations are impractical. One approach to reconstruct the histories of individual human cancers is to analyze the current genomic variation between its cells. The greater the variations, on average, the greater the time since the last clonal evolution cycle (‘‘a molecular clock hypothesis’’). Here we analyze passenger DNA methylation patterns from opposite sides of 12 primary human colorectal cancers (CRCs) to evaluate whether the variation (pairwise distances between epialleles) is consistent with a single clonal expansion after transformation. Methodology/Principal Findings: Data from 12 primary CRCs are compared to epigenomic data simulated under a single clonal expansion for a variety of possible growth scenarios. We find that for many different growth rates, a single clonal expansion can explain the population variation in 11 out of 12 CRCs. In eight CRCs, the cells from different glands are all equally distantly related, and cells sampled from the same tumor half appear no more closely related than cells sampled from opposite tumor halves. In these tumors, growth appears consistent with a single ‘‘symmetric’’ clonal expansion. In three CRCs, the variation in epigenetic distances was different between sides, but this asy