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: 3.84). 08/2006; 208(2):461-72. DOI: 10.1002/jcp.20685
Source: PubMed


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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    • "Thus drug-resistance in this case was probably generated in part by the clonal selection of a non-clonal variant of the drug-sensitive native carcinoma MS-751. This confirms a previous example for phenotypic variation by selection of a non-clonal chromosome by Heng et al. [51,56]. "
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    ABSTRACT: In 1952 Papanicolaou et al. first diagnosed and graded cervical carcinomas based on individual "abnormal DNA contents" and cellular phenotypes. Surprisingly current papilloma virus and mutation theories of carcinomas do not mention these individualities. The viral theory holds that randomly integrated, defective genomes of papilloma viruses, which are often untranscribed, cause cervical carcinomas with unknown cofactors 20--50 years after infection. Virus-free carcinomas are attributed to mutations of a few tumor-suppressor genes, especially the p53 gene. But the paradox of how a few mutations or latent defective viral DNAs would generate carcinomas with endless individual DNA contents, degrees of malignancies and cellular phenotypes is unsolved. Since speciation predicts individuality, we test here the theory that cancers are autonomous species with individual clonal karyotypes and phenotypes. This theory postulates that carcinogens induce aneuploidy. By unbalancing mitosis genes aneuploidy catalyzes chain reactions of karyotypic evolutions. Most such evolutions end with non-viable karyotypes but a few become new cancer karyotypes. Despite congenitally unbalanced mitosis genes cancer karyotypes are stabilized by clonal selections for cancer-specific autonomy. To test the prediction of the speciation theory that individual carcinomas have individual clonal karyotypes and phenotypes, we have analyzed here the phenotypes and karyotypes of nine cervical carcinomas. Seven of these contained papilloma virus sequences and two did not. We determined phenotypic individuality and clonality based on the morphology and sociology of carcinoma cells in vitro. Karyotypic individuality and clonality were determined by comparing all chromosomes of 20 karyotypes of carcinomas in three-dimensional arrays. Such arrays list chromosome numbers on the x-axis, chromosome copy numbers on the y-axis and the number of karyotypes arrayed on the z-axis. We found (1) individual clonal karyotypes and phenotypes in all nine carcinomas, but no virus-specific markers, (2) 1-to-1 variations between carcinoma-specific karyotypes and phenotypes, e.g. drug-resistance and cell morphology, (3) proportionality between the copy numbers of chromosomes and the copy numbers of hundreds of over- and under-expressed mRNAs, (4) evidence that tobacco-carcinogens induce cervical carcinomas via aneuploidy, consistent with the speciation theory. Since the individual clonal karyotypes of nine carcinomas correlated and co-varied 1-to-1 with complex individual transcriptomes and phenotypes, we have classical genetic and functional transcriptomic evidence to conclude that these karyotypes encode carcinomas - much like the clonal karyotypes that encode conventional species. These individual karyotypes explain the individual "DNA contents", the endless grades of malignancies and the complex individual transcriptomes and phenotypes of carcinomas.
    Molecular Cytogenetics 10/2013; 6(1):44. DOI:10.1186/1755-8166-6-44 · 2.14 Impact Factor
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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] "
    Oncogene and Cancer - From Bench to Clinic, 1st edited by Yahwardiah Siregar, 01/2013: chapter 7: pages 151-182; InTech - Croatia., ISBN: 978-953-51-0858-0
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