Analysis of Intratumor Heterogeneity and Clonal Somatic Evolution Using Whole-Exome Sequencing of Bulk Cancer DNA

• Activity Number: 574
• Type: Invited
• Date/Time: Wednesday, August 7, 2013 : 2:00 PM to 3:50 PM
• Sponsor: WNAR
• Author(s): Scott L. Carter*+
• Companies: The Broad Institute and MIT

Abstract

We present computational techniques for analyzing massively parallel sequencing data to measure the fraction of cancer cells harboring each somatic mutation and resolve subclonal cell populations. The method begins with calibration of sequencing read depths at each target region against a large set of normal controls. This is used to derive copy-ratio profiles of tumor samples with minimal distortion from regional biases. We then analyze allelic fractions at heterozygous SNP sites identified in the paired normal sample to derive allele-specific copy ratios directly from the sequencing data. These data, as well as allele fractions at somatic SNV sites, are then input into the ABSOLUTE method, which estimates the fraction of cancer and normal cells, the average ploidy of the malignant cells, and the absolute allelic copy numbers. This allows identification of subclonal mutations that are unlikely to be shared by all cancer cells in the sample. We present additional Bayesian clustering methods to study cancers sampled from the same individual at multiple timepoints, and demonstrate the evolution of subclones with distinct driver mutations that expanded following treatment.