Journal Article

An enhanced genetic model of colorectal cancer progression history

Yang, Lixing, Lee, Semin, Kucherlapati, Raju, Lee, Jake June-Koo, Wheeler, David A., Park, Peter J., Lee, Eunjung, Shinbrot, Eve, Wang, Su

2019

Overview

Background The classical genetic model of colorectal cancer presents APC mutations as the earliest genomic alterations, followed by KRAS and TP53 mutations. However, the timing and relative order of clonal expansion and other types of genomic alterations, such as genomic rearrangements, are still unclear. Results Here, we perform comprehensive bioinformatic analysis to dissect the relative timing of somatic genetic alterations in 63 colorectal cancers with whole-genome sequencing data. Utilizing allele fractions of somatic single nucleotide variants as molecular clocks while accounting for the presence of copy number changes and structural alterations, we identify key events in the evolution of colorectal tumors. We find that driver point mutations, gene fusions, and arm-level copy losses typically arise early in tumorigenesis; different mechanisms act on distinct genomic regions to drive DNA copy changes; and chromothripsis—clustered rearrangements previously thought to occur as a single catastrophic event—is frequent and may occur multiple times independently in the same tumor through different mechanisms. Furthermore, our computational approach reveals that, in contrast to recent studies, selection is often present on subclones and that multiple evolutionary models can operate in a single tumor at different stages. Conclusion Combining these results, we present a refined tumor progression model which significantly expands our understanding of the tumorigenic process of human colorectal cancer.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adenomatous polyposis coli / alleles / Aneuploidy / Animal Genetics and Genomics / Bioinformatics / Biomedical and Life Sciences / Cancer / carcinogenesis / Chromosomes / Chromothripsis / Cohort Studies / Colorectal cancer / colorectal neoplasms / Colorectal Neoplasms - genetics / Colorectal Neoplasms - pathology / Copy number / Disease Progression / DNA / DNA Copy Number Variations - genetics / Epigenetics / Evolution / Evolutionary Biology / Gene Dosage / genetic models / Genomes / Genomics / Human Genetics / Humans / Kataegis / Life Sciences / Mann-Whitney U test / Microbial Genetics and Genomics / Models, Genetic / Mutation / Mutation - genetics / neoplasm progression / p53 Protein / Plant Genetics and Genomics / Point mutation / Tumor evolution / Tumor heterogeneity / Tumorigenesis / Tumors / Whole genome sequencing / Yeast