Inferring the Chromosomal Landscape of the First Few Cell Divisions in Colorectal Adenomas

• Activity Number: 501
• Type: Invited
• Date/Time: Wednesday, August 7, 2013 : 10:30 AM to 12:20 PM
• Sponsor: General Methodology
• Author(s): Kimberly D Siegmund*+ and Paul Marjoram and Darryl Shibata
• Companies: University of Southern California and University of Southern California and University of Southern California
• Keywords: cancer growth ; Approximate Bayesian Computation ; phylogeny

Abstract

Intratumor heterogeneity, or the presence of different mutations in different cells of the same tumor, is common in human tumors. Tumor growth, just like phylogeny and human development, requires genome replication, which generates intratumor heterogeneity from replication errors. Chromosome copy number alterations (CNAs) in the first initiating cell should appear in all descendant tumor cells, and CNAs that appear later in growth, in progressively smaller subsets ('private'). By sampling individual glands that carry mixtures of adjacent cells with different CNAs(~8,000 cells/gland) from opposite sides of a tumor, gland average CNA and corresponding B-allele frequency (BAF) combinations can convey information about the chromosomal landscape of the original transformed cell, and the private CNAs that arise during the first few cell divisions. We have analyzed DNA in 8 individual glands from three colon adenomas using Illumina SNP microarrays, and estimated gland chromosomal CNs and BAFs. We apply approximate Bayesian computation, a simulation-based method, to model adenoma growth under a variety of evolutionary scenarios, and identify models that fit the CN/BAF observed in our data.