Genetic instability and the quasispecies model

Brumer, Yisroel; Michor, Franziska; Shakhnovich, Eugene I.

doi:10.1016/j.jtbi.2005.11.018

Cited by 36 publications

(34 citation statements)

References 24 publications

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“…MIN and CIN phenotypes are mutually exclusive. 11,50 This suggests that a cell can accommodate a finite amount of genomic instability and excess instability can be detrimental to the cell. It also supports the possibility that processes responsible for induction of MIN, at the same time inhibit those that give rise to CIN.…”

mentioning

confidence: 99%

CIN by WNT: Growth Pathways, Mitotic Control and Chromosomal Instability in Cancer

Hadjihannas

Behrens²

2006

Cell Cycle

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confidence: 99%

CIN by WNT: Growth Pathways, Mitotic Control and Chromosomal Instability in Cancer

Hadjihannas

Behrens²

2006

Cell Cycle

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“…Other tumors display genetic instability in the form of CIN (chromosomal instability) with a wide variation in chromosome number and other chromosomal instability 19,28 . The possibility that such instability can be treated, to a first approximation, through the inclusion of recombination 38,39 and simulation techniques is the subject of future research 40 . Previous results in these areas provide reason to believe that the underlying dynamics for models of CIN tumors should provide similar results to those obtained here.…”

Section: Discussionmentioning

confidence: 99%

Importance of DNA repair in tumor suppression

Brumer

Shakhnovich

2004

Phys. Rev. E

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The transition from a normal to cancerous cell requires a number of highly specific mutations that affect cell cycle regulation, apoptosis, differentiation, and many other cell functions. One hallmark of cancerous genomes is genomic instability, with mutation rates far greater than those of normal cells. In microsatellite instability (MIN tumors), these are often caused by damage to mismatch repair genes, allowing further mutation of the genome and tumor progression. These mutation rates may lie near the error catastrophe found in the quasispecies model of adaptive RNA genomes, suggesting that further increasing mutation rates will destroy cancerous genomes. However, recent results have demonstrated that DNA genomes exhibit an error threshold at mutation rates far lower than their conservative counterparts. Furthermore, while the maximum viable mutation rate in conservative systems increases indefinitely with increasing master sequence fitness, the semiconservative threshold plateaus at a relatively low value. This implies a paradox, wherein inaccessible mutation rates are found in viable tumor cells. In this paper, we address this paradox, demonstrating an isomorphism between the conservatively replicating (RNA) quasispecies model and the semiconservative (DNA) model with post-methylation DNA repair mechanisms impaired. Thus, as DNA repair becomes inactivated, the maximum viable mutation rate increases smoothly to that of a conservatively replicating system on a transformed landscape, with an upper bound that is dependent on replication rates. On a specific single fitness peak landscape, the repair-free semiconservative system is shown to mimic a conservative system exactly . We postulate that inactivation of post-methylation repair mechanisms are fundamental to the progression of a tumor cell and hence these mechanisms act as a method for prevention and destruction of cancerous genomes.

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“…The evolutionary dynamics of cancer initiation and progression has been theoretically approached with mathematical deterministic equations (Michor et al 2005Abbott and Michor 2006;Garner et al 2006) or with stochastic models (Roeder et al 2006;Brumer et al 2006;Iwasa et al 2004;Michor et al 2003;Dingli and Michor 2006;Komarova and Wodarz 2007;Zhdanov 2008;Pizzolato et al 2009), both using the basic idea that cancer arises when a single non-differentiated cell experiences multiple mutations, as confirmed by numerous studies on cancer genetics (Knudson 2001;Frank et al 2003). These studies describe the temporal evolution of the level of BCR-ABL positive cells, observed in clinical investigations on patients treated with imatinib, in terms of a partial or total failure of the drug efficacy on cancer cells.…”

Section: Model Of CML Evolutionmentioning

confidence: 99%

Stochastic dynamics of leukemic cells under an intermittent targeted therapy

et al. 2011

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The evolutionary dynamics of cancerous cell populations in a model of Chronic Myeloid Leukemia (CML) is investigated in the presence of an intermittent targeted therapy. Cancer development and progression is modeled by simulating the stochastic evolution of initially healthy cells which can experience genetic mutations and modify their reproductive behavior, becoming leukemic clones. Front line therapy for the treatment of patients affected by CML is based on the administration of tyrosine kinase inhibitors, namely imatinib (Gleevec) or, more recently, dasatinib or nilotinib. Despite the fact that they represent the first example of a successful molecular targeted therapy, the development of resistance to these drugs is observed in a proportion of patients, especially those in advanced stages. In this study, we simulate an imatinib-like treatment of CML by modifying the fitness and the death rate of cancerous cells and describe the several scenarios in the evolutionary dynamics of white blood cells as a consequence of the efficacy of the different modeled therapies. The patient response to the therapy is investigated by simulating a drug administration following a continuous or pulsed time scheduling. A permanent disappearance of leukemic clones is achieved with a continuous therapy. This theoretical behavior is in a good agreement with that observed in previous clinical investigations. However, these findings demonstrate that an intermittent therapy could represent a valid alternative in patients with high risk of toxicity. A suitable tuned pulsed therapy can also reduce the probability of developing resistance.

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Genetic instability and the quasispecies model

Cited by 36 publications

References 24 publications

CIN by WNT: Growth Pathways, Mitotic Control and Chromosomal Instability in Cancer

CIN by WNT: Growth Pathways, Mitotic Control and Chromosomal Instability in Cancer

Importance of DNA repair in tumor suppression

Stochastic dynamics of leukemic cells under an intermittent targeted therapy

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