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Cold Spring Harb Perspect Med. 2017 Jun 1;7(6). pii: a029611. doi: 10.1101/cshperspect.a029611.

Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution.

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Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065.
Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065.
Division of Hematology and Medical Oncology and the Department of Physiology and Biophysics, Weill Cornell Medicine, New York, New York 10021.
Core member of the New York Genome Center, New York, New York 10013.


Large-scale, massively parallel sequencing of human cancer samples has revealed tremendous genetic heterogeneity within individual tumors. Indeed, tumors are composed of an admixture of diverse subpopulations-subclones-that vary in space and time. Here, we discuss a principal driver of clonal diversification in cancer known as chromosomal instability (CIN), which complements other modes of genetic diversification creating the multilayered genomic instability often seen in human cancer. Cancer cells have evolved to fine-tune chromosome missegregation rates to balance the acquisition of heterogeneity while preserving favorable genotypes, a dependence that can be exploited for a therapeutic benefit. We discuss how whole-genome doubling events accelerate clonal evolution in a subset of tumors by providing a viable path toward favorable near-triploid karyotypes and present evidence for CIN-induced clonal speciation that can overcome the dependence on truncal initiating events.

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