OCT 10, 2019 9:00 AM PDT

Dynamic evolution of unstable genomes: insights from in vitro experiments and cancer genome analysis

C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • Assistant Professor, Biomedical Informatics, Harvard Medical School , and Assistant Professor, Biostatistics & Computational Biology, Dana-Farber Cancer Institute
    Biography
      Cheng-Zhong Zhang obtained a Ph.D. in Chemical Engineering with a minor in Physics from Caltech. He received postdoctoral training in single-molecule biophysics in Timothy Springer's laboratory at Harvard Medical School and subsequently worked on single-cell genomics and cancer biology in Matthew Meyerson's laboratory at the Broad Institute of Harvard and MIT and at Dana-Farber Cancer Institute. He combines single-cell genomic analysis and cell biology to study genome evolution and phenotypic variation. Currently he focuses on the mechanisms and the transcriptional consequences of chromosomal abnormalities, such as rearrangement and aneuploidy, and how such events may promote tumor development.

    Abstract

    Copy-number alterations and chromosomal translocations are widespread in cancer and frequently causing oncogenic mutations that drive tumorigenesis and therapy resistance. Despite their prevalence, how these alterations arise during tumor development remains a mystery. We have gained significant insight into this question by analyzing alterations in unstable genomes at the single-cell level over one and multiple generations. Our results indicate that even a single broken chromosome in an ancestor cell can cause highly dynamic evolution and generate extensive genetic diversity in the progeny population, giving rise to all forms of alterations in cancer genomes, including focal amplification and deletion, arm-level copy-number changes, and complex rearrangements. We hypothesize that such genetic diversity may fuel the transition from pre-malignancy to cancer and present preliminary evidence from the analyses of Barrett’s Esophagus as a precursor to esophageal adenocarcinoma. Together, our results suggest that a few simple mechanisms of chromosomal evolution may be sufficient to create the enormous complexity of cancer genomes and the evolution of unstable genomes may be not totally random after all.

    Learning objectives:

    1. What makes an unstable chromosome and how does it trigger genome evolution?
    2. How does genome instability and genetic diversity promote tumor development?


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