Browsing by Subject "models of evolution"

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    Inferring paths of neoplastic transformation from analysis of colorectal cancer with residual polyp of origin
    (2017-06) Kim, Minsoo
    Besides the classical evolutionary model of colorectal cancer (CRC) defined by the stepwise accumulation of mutations in which normal epithelium transforms through an intermediary polyp stage to cancer, few studies have proposed alternative modes of evolution (MOE): early eruptive subclonal expansion, branching of the subclones in parallel evolution, and neutral evolution. However, frequencies of MOEs and their connection to mutational characteristics of cancer remain elusive. In this study, we analyzed patterns of somatic single nucleotide variations and DNA copy number aberrations (CNAs) in CRC with residual polyp of origin and in cancer free polyps from 27 patients in order to determine this relationship. For each MOE we defined an expected pattern with characteristic features of allele frequency distributions for SNVs in cancers and their matching adenomas. From these distinct patterns, we then assigned an MOE to each CRC case and found that stepwise progression was the most common (70% of cases). We found that CRC with the same MOE may exhibit different mutational spectra, suggesting that different mutational mechanisms can result in the same MOE. Inversely, cancers with different MOEs can have the same mutational spectrum, suggesting that the same mutational mechanism can lead to different MOEs. The types of somatic substitutions, distribution of CNAs across genome, and mutated pathways did not correlate with MOEs. As this could be due to small sample size, these relations warrant further investigation. Our study paves the way to connect MOE with clinical and mutational characteristics not only in CRC but also to neoplastic transformation in other cancers.