Assessing intratumor heterogeneity and evolutionary distance in exome sequencing of colon cancer.

Abstract

590 Background: Carcinogenesis is considered to be an evolutionary process by natural selection of cell clones which have acquired advantageous heritable characteristics. This adaption process, which resembles Darwin’s evolutionary theory, has also been suggested as a potential mechanism promoting resistance to anti-cancer treatment. Methods: We performed whole exome sequencing of four colon cancers at five morphologically different loci of the primary tumor tissue. To investigate intratumor heterogeneity we conducted structural variant analysis, copy number analysis and ploidy profiling. We propose an evolutionary distance of the tumor samples based on a distance function in copy number space. Results: Copy number and phylogenetic analysis demonstrated substantial intratumor heterogeneity, with all 20 samples (5 loci for 4 tumors) possessing a unique copy number profile. Our analysis further revealed cancer-specific, tumor-specific and locus-specific copy number variants. We found that at least one copy of 18q, including the genes DCC and SMAD4, as well as 8p, carrying the CSMD1 gene, was missing in all tumors. Additionally, gains of chromosome 7,8q, 13q, 20q and losses of 4q and 21q were frequent. Using our distance measure in copy number space, phylogenetic analysis grouped together the five loci of one tumor and showed their evolutionary branching. We found that our distance measure in copy number space is superior to a distance measure in SNV space for colon cancer. Conclusions: Our analysis reveals that the landscape of the tumor genome cannot be captured by single tumor-biopsy, which is one of the challenges to personalized-medicine as heterogeneity can lead to therapeutic failures. However, there can be characteristics of the tumor genomes that are stable across samples which can potentially be used as biomarkers. Nonetheless variability of copy number profiles of colorectal cancers might suggest a personalized therapy.