title: Ancestral inference in tumors: how much can we know?
abstract: 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.
authors.affiliation: Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: junsongz@usc.edu.
authors.forename: Junsong
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: kims@usc.edu.
authors.forename: Kimberly D
authors.initials: KD
authors.lastname: Siegmund
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA. Electronic address: dshibata@usc.edu.
authors.forename: Darryl
authors.initials: D
authors.lastname: Shibata
authors.affiliation: 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. Electronic address: pmarjora@usc.edu.
authors.forename: Paul
authors.initials: P
authors.lastname: Marjoram
mesh_terms: D001499:Bayes Theorem; D049109:Cell Proliferation / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D019295:Computational Biology; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D019143:Evolution, Molecular; D018740:Genetic Heterogeneity; D015894:Genome, Human; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA
keywords: Ancestry; Approximate Bayesian computation; Methylation; Methylation error rate; Number of cancer stem cells