Stochastic cancer progression driven by non-clonal chromosome aberrations.
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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ABSTRACT: Abstract Ovarian cancer is the fifth leading cause of death among women worldwide. Characterized by complex etiology and multi-level heterogeneity, its origins are not well understood. Intense research efforts over the last decade have furthered our knowledge by identifying multiple risk factors that are associated with the disease. However, it is still unclear how genetic heterogeneity contributes to tumor formation, and more specifically, how genome-level heterogeneity acts as the key driving force of cancer evolution. Most current genomic approaches are based on 'average molecular profiling.' While effective for data generation, they often fail to effectively address the issue of high level heterogeneity because they mask variation that exists in a cell population. In this synthesis, we hypothesize that genome-mediated cancer evolution can effectively explain diverse factors that contribute to ovarian cancer. In particular, the key contribution of genome replacement can be observed during major transitions of ovarian cancer evolution including cellular immortalization, transformation, and malignancy. First, we briefly review major updates in the literature, and illustrate how current gene-mediated research will offer limited insight into cellular heterogeneity and ovarian cancer evolution. We next explain a holistic framework for genome-based ovarian cancer evolution and apply it to understand the genomic dynamics of a syngeneic ovarian cancer mouse model. Finally, we employ single cell assays to further test our hypothesis, discuss some predictions, and report some recent findings.Systems biology in reproductive medicine 10/2013; · 1.85 Impact Factor
- Proceedings of the National Academy of Sciences 01/2014; · 9.74 Impact Factor
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ABSTRACT: Cells are constantly exposed to various internal and external stresses. The importance of cellular stress and its implication to disease conditions have become popular research topics. Many ongoing investigations focus on the sources of stress, their specific molecular mechanisms and interactions, especially regarding their contributions to many common and complex diseases through defined molecular pathways. Numerous molecular mechanisms have been linked to endoplasmic reticulum stress along with many unexpected findings, drastically increasing the complexity of our molecular understanding and challenging how to apply individual mechanism-based knowledge in the clinic. A newly emergent genome theory searches for the synthesis of a general evolutionary mechanism that unifies different types of stress and functional relationships from a genome-defined system point of view. Herein, we discuss the evolutionary relationship between stress and somatic cell adaptation under physiological, pathological, and somatic cell survival conditions, the multiple meanings to achieve adaptation and its potential trade-off. In particular, we purposely defocus from specific stresses and mechanisms by redirecting attention toward studying underlying general mechanisms.Frontiers in Genetics 01/2014; 5:92.