How Chaotic Is Genome Chaos?

Shapiro, James A.

doi:10.3390/cancers13061358

Cited by 12 publications

(9 citation statements)

References 185 publications

(263 reference statements)

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“…Such plasticity, or heterogeneity, is the lifeline for cancer cells, as it helps cancer cells to survive and become dominant under multiple levels of constraints. Constant change is the winning strategy for cancer cells, and genome instability is a powerful mechanism that allows both the survival (by changing genome structure within the macroevolutionary phase) and fitness (by changing gene mutation/epigenetic profile within the microevolutionary phase) of cancer cells [11][12][13][14]. Genomic instability can give rise to gene mutations, chromosomal translocations, alternations of copy number, deletions, and inversions of pieces of DNA [15].…”

Section: Introductionmentioning

confidence: 99%

Emerging Role of Chimeric RNAs in Cell Plasticity and Adaptive Evolution of Cancer Cells

Mukherjee

Heng

Frenkel‐Morgenstern

2021

Cancers

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Gene fusions can give rise to somatic alterations in cancers. Fusion genes have the potential to create chimeric RNAs, which can generate the phenotypic diversity of cancer cells, and could be associated with novel molecular functions related to cancer cell survival and proliferation. The expression of chimeric RNAs in cancer cells might impact diverse cancer-related functions, including loss of apoptosis and cancer cell plasticity, and promote oncogenesis. Due to their recurrence in cancers and functional association with oncogenic processes, chimeric RNAs are considered biomarkers for cancer diagnosis. Several recent studies demonstrated that chimeric RNAs could lead to the generation of new functionality for the resistance of cancer cells against drug therapy. Therefore, targeting chimeric RNAs in drug resistance cancer could be useful for developing precision medicine. So, understanding the functional impact of chimeric RNAs in cancer cells from an evolutionary perspective will be helpful to elucidate cancer evolution, which could provide a new insight to design more effective therapies for cancer patients in a personalized manner.

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Section: Introductionmentioning

confidence: 99%

Emerging Role of Chimeric RNAs in Cell Plasticity and Adaptive Evolution of Cancer Cells

Mukherjee

Heng

Frenkel‐Morgenstern

2021

Cancers

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“…Additionally, the share repeats intermediate, bending and loop forming tri-dimensional structures, binding sites for charged protein electron emitted signaling pathway, and a closed lock selection site of the foreign DNA transfer end-joining recombination mechanism [36, 41 and 57]. The specificity of the target organ rejection now, could be called out through the AC-reach repeats stoichiometry thus, bend and loop tri-dimensional structures [194], source of cell-to-cell signaling the homing roadway [33, 36, 39, 41, 57, 172]. Occasionally, groups of kDNA minicircle sequence integration mutations, and polygenic modifications thereof, may explain the lymphocyte activation and the rejection of the target host’s cells, showing the multifaceted clinical manifestations translated into the pathology.…”

Section: Discussionmentioning

confidence: 99%

The Trypanosoma cruzi kinetoplast DNA minicircle sequences transfer biomarker of the multidrug treatment of Chagas disease

Teixeira

Sousa

Gomes

et al. 2021

Preprint

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BackgroundThe Trypanosoma cruzi infection renders the transfer of the mitochondrion kinetoplast DNA minicircle sequences into the host’s genome. The Aves are refractory to the infection, but chicks hatched from the T. cruzi inoculated eggs integrate the DNA minicircle sequences into the germ line cells. Rabbits, mice and chickens with the minicircle sequences mutations develop the Chagas cardiomyopathy and the DNA transfer underpins the heart disease.MethodologyThe PCR with the specific primer sets revealed the Protist nuclear DNA and the kinetoplast DNA in the agarose gels bands probed with the radiolabel specific sequences from tissues of the T. cruzi-infected rabbits and of the mice. A target- primer TAIL-PCR amplification employing primer sets from the chickens, rabbits and mice, in combination with primer sets from the the T. cruzi kinetoplast minicircle sequences was used. This approach led us to disclose the integration sites of the kinetoplast DNA biomarker, then, used to monitor the effect of multidrug treatment of the T. cruzi infected mice.Principal findingsThe Southern hybridization, clone and sequence of the amplification products revealed the DNA minicircle sequences integrations sites in the LINE transposable elements. An array of inhibitors of eukaryote cells division was used to arrest the DNA transfer. It was shown that nine out of 12 inhibitors prevented the kinetoplast DNA integration into the macrophage genome. The multidrug treatment of the acutely T. cruzi-infected mice with Benznidazole, Azidothymidine and Ofloxacin lessened circa 2.5-fold the rate of the minicircle sequences integrations in the mouse genome and inhibited the rejection of the target heart cells.Conclusion and significanceThe T. cruzi mitochondrion kinetoplast minicircle sequences transfer driven pathogenesis of Chagas disease is an ancient Cross-Kingdom DNA phenomenon of evolution and, therefore, paradigm research with effective purposing inhibitors is needed.Authors summaryChagas disease is considered the main cause of human heart failure in the Western Hemisphere. The treatment of the clinically manifested Chagas heart disease is considered unsatisfactory. Perhaps the most important problem in the field of Chagas disease is determination of the pathogenesis of the target heart cells lysis. We showed the transfer of the T. cruzi kDNA minicircle sequences into the genome of rabbits and mice, and to Bird refractory to the infections. The inoculation of a few T. cruzi in the fertile chicken eggs renders the kDNA sequences integration in the stem cells. Interestingly, the chicks that hatched retain the kDNA and develop the Chagas-like cardiomyopathy indistinguishable to that in the rabbits and mice. This result prompted the multidrug treatment of the Chagas heart disease with inhibitors of the eukaryotic cells division. We showed that nine out of 12 inhibitors prevented the transfer of the kDNA mutations into the macrophage genome, and that the treatment of the acutely T. cruzi-infected mice with Benznidazole + Ofloxacin + Azidothymidine lowered circa 2.5-fold the rate of the mutations in the chromosomes. These findings translated to the pathology showing inhibition of the heart lesions in the treated T. cruzi-infected mice. We suggest purposing new inhibitors should be tested to overturning the Chagas heart disease.

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“…In contrast, unexpectedly, chaotic genomes have commonly been detected from cancers in the Cancer Genome Project [ 92 , 93 , 94 ]. Although many different new terms were employed to describe the phenomena, previous cytogenetic discoveries of genome chaos were confirmed.…”

Section: Newly Emergent Genomic and Evolutionary Conceptsmentioning

confidence: 99%

Genome Chaos, Information Creation, and Cancer Emergence: Searching for New Frameworks on the 50th Anniversary of the “War on Cancer”

Heng

2021

Genes

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The year 2021 marks the 50th anniversary of the National Cancer Act, signed by President Nixon, which declared a national “war on cancer.” Powered by enormous financial support, this past half-century has witnessed remarkable progress in understanding the individual molecular mechanisms of cancer, primarily through the characterization of cancer genes and the phenotypes associated with their pathways. Despite millions of publications and the overwhelming volume data generated from the Cancer Genome Project, clinical benefits are still lacking. In fact, the massive, diverse data also unexpectedly challenge the current somatic gene mutation theory of cancer, as well as the initial rationales behind sequencing so many cancer samples. Therefore, what should we do next? Should we continue to sequence more samples and push for further molecular characterizations, or should we take a moment to pause and think about the biological meaning of the data we have, integrating new ideas in cancer biology? On this special anniversary, we implore that it is time for the latter. We review the Genome Architecture Theory, an alternative conceptual framework that departs from gene-based theories. Specifically, we discuss the relationship between genes, genomes, and information-based platforms for future cancer research. This discussion will reinforce some newly proposed concepts that are essential for advancing cancer research, including two-phased cancer evolution (which reconciles evolutionary contributions from karyotypes and genes), stress-induced genome chaos (which creates new system information essential for macroevolution), the evolutionary mechanism of cancer (which unifies diverse molecular mechanisms to create new karyotype coding during evolution), and cellular adaptation and cancer emergence (which explains why cancer exists in the first place). We hope that these ideas will usher in new genomic and evolutionary conceptual frameworks and strategies for the next 50 years of cancer research.

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How Chaotic Is Genome Chaos?

Cited by 12 publications

References 185 publications

Emerging Role of Chimeric RNAs in Cell Plasticity and Adaptive Evolution of Cancer Cells

Emerging Role of Chimeric RNAs in Cell Plasticity and Adaptive Evolution of Cancer Cells

The Trypanosoma cruzi kinetoplast DNA minicircle sequences transfer biomarker of the multidrug treatment of Chagas disease

Genome Chaos, Information Creation, and Cancer Emergence: Searching for New Frameworks on the 50th Anniversary of the “War on Cancer”

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