title: Genome chaos: survival strategy during crisis.
abstract: Genome chaos, a process of complex, rapid genome re-organization, results in the formation of chaotic genomes, which is followed by the potential to establish stable genomes. It was initially detected through cytogenetic analyses, and recently confirmed by whole-genome sequencing efforts which identified multiple subtypes including "chromothripsis", "chromoplexy", "chromoanasynthesis", and "chromoanagenesis". Although genome chaos occurs commonly in tumors, both the mechanism and detailed aspects of the process are unknown due to the inability of observing its evolution over time in clinical samples. Here, an experimental system to monitor the evolutionary process of genome chaos was developed to elucidate its mechanisms. Genome chaos occurs following exposure to chemotherapeutics with different mechanisms, which act collectively as stressors. Characterization of the karyotype and its dynamic changes prior to, during, and after induction of genome chaos demonstrates that chromosome fragmentation (C-Frag) occurs just prior to chaotic genome formation. Chaotic genomes seem to form by random rejoining of chromosomal fragments, in part through non-homologous end joining (NHEJ). Stress induced genome chaos results in increased karyotypic heterogeneity. Such increased evolutionary potential is demonstrated by the identification of increased transcriptome dynamics associated with high levels of karyotypic variance. In contrast to impacting on a limited number of cancer genes, re-organized genomes lead to new system dynamics essential for cancer evolution. Genome chaos acts as a mechanism of rapid, adaptive, genome-based evolution that plays an essential role in promoting rapid macroevolution of new genome-defined systems during crisis, which may explain some unwanted consequences of cancer treatment.
authors.affiliation: Center for Molecular Medicine and Genetics; Wayne State University School of Medicine; Detroit, MI USA.
authors.forename: Guo
authors.initials: G
authors.lastname: Liu
authors.affiliation: Center for Molecular Medicine and Genetics; Wayne State University School of Medicine; Detroit, MI USA.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Stevens
authors.affiliation: Center for Molecular Medicine and Genetics; Wayne State University School of Medicine; Detroit, MI USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Horne
authors.affiliation: Center for Molecular Medicine and Genetics; Wayne State University School of Medicine; Detroit, MI USA.
authors.forename: Batoul Y
authors.initials: BY
authors.lastname: Abdallah
authors.affiliation: SeeDNA Inc; Windsor, Ontario Canada.
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Ye
authors.affiliation: Center for Molecular Medicine and Genetics; Wayne State University School of Medicine; Detroit, MI USA.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Bremer
authors.affiliation: Department of Hematology Oncology; Karmanos Cancer Institute; Detroit, MI USA.
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Ye
authors.affiliation: Division of Molecular Radiation Biology, Department of Radiation Oncology; The University of Texas Southwestern Medical Center; Dallas TX USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Chen
authors.affiliation: Center for Molecular Medicine and Genetics; Wayne State University School of Medicine; Detroit, MI USA; Department of Pathology; Wayne State University School of Medicine; Detroit, MI USA.
authors.forename: Henry H
authors.initials: HH
authors.lastname: Heng
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D043171:Chromosomal Instability; D002869:Chromosome Aberrations; D004249:DNA Damage; D059766:DNA End-Joining Repair; D004317:Doxorubicin / Q000494:pharmacology; D016678:Genome; D006801:Humans; D059785:Karyotype; D051379:Mice; D016685:Mitomycin / Q000494:pharmacology; D059467:Transcriptome
chemical_list: D000970:Antineoplastic Agents; D016685:Mitomycin; D004317:Doxorubicin
keywords: cancer evolution; chromoplexy; chromosome fragmentation; chromothripsis; genome chaos; genome theory; karyotypic chaos; macro-cellular evolution; system inheritance