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Stochastic cancer progression driven by non-clonal chromosome aberrations

Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Journal of Cellular Physiology (Impact Factor: 3.87). 08/2006; 208(2):461-72. DOI: 10.1002/jcp.20685
Source: PubMed

ABSTRACT Cancer research has previously focused on the identification of specific genes and pathways responsible for cancer initiation and progression based on the prevailing viewpoint that cancer is caused by a stepwise accumulation of genetic aberrations. This viewpoint, however, is not consistent with the clinical finding that tumors display high levels of genetic heterogeneity and distinctive karyotypes. We show that chromosomal instability primarily generates stochastic karyotypic changes leading to the random progression of cancer. This was accomplished by tracing karyotypic patterns of individual cells that contained either defective genes responsible for genome integrity or were challenged by onco-proteins or carcinogens that destabilized the genome. Analysis included the tracing of patterns of karyotypic evolution during different stages of cellular immortalization. This study revealed that non-clonal chromosomal aberrations (NCCAs) (both aneuploidy and structural aberrations) and not recurrent clonal chromosomal aberrations (CCAs) are directly linked to genomic instability and karyotypic evolution. Discovery of "transitional CCAs" during in vitro immortalization clearly demonstrates that karyotypic evolution in solid tumors is not a continuous process. NCCAs and their dynamic interplay with CCAs create infinite genomic combinations leading to clonal diversity necessary for cancer cell evolution. The karyotypic chaos observed within the cell crisis stage prior to establishment of the immortalization further supports the ultimate importance of genetic aberrations at the karyotypic or genome level. Therefore, genomic instability generated NCCAs are a key driving force in cancer progression. The dynamic relationship between NCCAs and CCAs provides a mechanism underlying chromosomal based cancer evolution and could have broad clinical applications.

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    • "DNA methyltransferase deficient cells are chromosomally unstable [154] [155], and mice models have demonstrated that genomewide DNA hypomethylation can induce tumors [156] [157] [158]. Thus, a specific effect of oncoproteins is to cause aneuploidization [50] and the elevation of stochastic CIN [10] "
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    • "DNA methyltransferase deficient cells are chromosomally unstable [154] [155], and mice models have demonstrated that genomewide DNA hypomethylation can induce tumors [156] [157] [158]. Thus, a specific effect of oncoproteins is to cause aneuploidization [50] and the elevation of stochastic CIN [10] "
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    • "For example, when studying the level of genome variations during the in vitro immortalization process, two additional cutoff lines were used (1% and 10%), the overall patterns of punctuated and stepwise phases of karyotypic evolution were the same as the 4% cutoff line (when the genome is unstable, the level of NCCAs often reaches over 20–50%). In our immortalization model, when the cell population reached the unstable phase, NCCA levels were 100%, regardless of which cut off line was used to separate CCAs and NCCAs (Heng et al., 2006b). In normal lymphocytes (based on both human and mouse data), the level of structural NCCAs is very low, in the range of 0.1–2%. "
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    ABSTRACT: Cancer progression represents an evolutionary process where overall genome level changes reflect system instability and serve as a driving force for evolving new systems. To illustrate this principle it must be demonstrated that karyotypic heterogeneity (population diversity) directly contributes to tumorigenicity. Five well characterized in vitro tumor progression models representing various types of cancers were selected for such an analysis. The tumorigenicity of each model has been linked to different molecular pathways, and there is no common molecular mechanism shared among them. According to our hypothesis that genome level heterogeneity is a key to cancer evolution, we expect to reveal that the common link of tumorigenicity between these diverse models is elevated genome diversity. Spectral karyotyping (SKY) was used to compare the degree of karyotypic heterogeneity displayed in various sublines of these five models. The cell population diversity was determined by scoring type and frequencies of clonal and non-clonal chromosome aberrations (CCAs and NCCAs). The tumorigenicity of these models has been separately analyzed. As expected, the highest level of NCCAs was detected coupled with the strongest tumorigenicity among all models analyzed. The karyotypic heterogeneity of both benign hyperplastic lesions and premalignant dysplastic tissues were further analyzed to support this conclusion. This common link between elevated NCCAs and increased tumorigenicity suggests an evolutionary causative relationship between system instability, population diversity, and cancer evolution. This study reconciles the difference between evolutionary and molecular mechanisms of cancer and suggests that NCCAs can serve as a biomarker to monitor the probability of cancer progression.
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