Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution

Abstract

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.

Transgenerationally Precipitated Meiotic Chromosome Instability Fuels Rapid Karyotypic Evolution and Phenotypic Diversity in an Artificially Constructed Allotetraploid Wheat (AADD)

“…2013; Bakhoum and Landau 2017). Complex karyotypic heterogeneity in human somatic cells, usually including intertwined numerical and structural chromosome abnormalities, is a defining feature of many types of cancers, and is increasingly recognized as a principal driver of both tumorigenesis and metastasis (Burrell et al.…”

“…Notably, evolved cancer cells usually converge to a near-triploid chromosome constitution with numerous structural changes, and which is often preceded by a WGD event (Dewhurst et al. 2014; Bakhoum and Landau 2017). Not surprisingly, efforts to elucidate the mechanistic basis of karyotypic instability as well as its biological impacts on cancer genesis and progression has become a central theme in biomedical research (Burrell et al.…”

“…Not surprisingly, efforts to elucidate the mechanistic basis of karyotypic instability as well as its biological impacts on cancer genesis and progression has become a central theme in biomedical research (Burrell et al. 2013; Bakhoum and Landau 2017). …”

“…Thus, persistently ongoing alterations of chromosome number and structure, that is, numerical and structural chromosome instability (CIN) (Dion-Cote et al. 2015; Bakhoum and Landau 2017), has severe phenotypic and fitness consequences and may lead to species extinction or catalyze saltational evolution. Somatic CIN is increasingly recognized as a central player in tumorigenesis and cancer metastasis (Dewhurst et al.…”

Flexible Cancer-Associated Chromatin Configuration (CACC) Might Be the Fundamental Reason Why Cancer Is So Difficult to Cure

“…However, the mechanism by which heterogeneous cancer cells or subclones in cancer cell populations are produced is not fully elucidated. The mainstream viewpoints blame genome instability for being the cause of cancer heterogeneity [3] [4], but we think that genome instability is only a superficial description about cancer genome, not a mechanism of how cancer heterogeneity is generated. Furthermore, we don't think that heterogeneity is the fundamental obstacle to beating cancer.…”