Efficiency of carcinogenesis with and without a mutator mutation

Abstract

Carcinogenesis involves the acquisition of multiple genetic changes altering various cellular phenotypes. These changes occur within the fixed time period of a human lifespan, and mechanisms that accelerate this process are more likely to result in clinical cancers. Mutator mutations decrease genome stability and, hence, accelerate the accumulation of random mutations, including those in oncogenes and tumor suppressor genes. However, if the mutator mutation is not in itself oncogenic, acquiring that mutation would add an extra, potentially time-consuming step in carcinogenesis. We present a deterministic mathematical model that allows quantitative prediction of the efficiency of carcinogenesis with and without a mutator mutation occurring at any time point in the process. By focusing on the ratio of probabilities of pathways with and without mutator mutations within cell lineages, we can define the frequency or importance of mutator mutations in populations independently of absolute rates and circumvent the question of whether mutator mutations are ''necessary'' for cancers to evolve within a human lifetime. We analyze key parameters that predict the relative contribution of mutator mutants in carcinogenesis. Mechanisms of carcinogenesis involving mutator mutations are more likely if they occur early. Involvement of mutator mutations in carcinogenesis is favored by an increased initial mutation rate, by greater fold-increase in mutation rate due to the mutator mutation, by increased required steps in carcinogenesis, and by increased number of cell generations to the development of cancer.cancer ͉ mathematical model ͉ mutator hypothesis T he development of a cancer requires multiple steps as suggested by epidemiologic data and animal models (1-5). At least some of these steps are believed to involve oncogenic mutations or other genetic changes.The mutator hypothesis originally stated that mutations in DNA polymerases and DNA repair enzymes would play a critical role in carcinogenesis by accelerating the acquisition of oncogenic mutations (6). This concept has been broadened to include a variety of mutator mutations that create genetic instability by mechanisms including microsatellite instability, chromosomal instability, and aberrations of checkpoint control (7-10).An alternative hypothesis is that enhanced rates of genetic instability are not necessary for carcinogenesis and that cancer arises from mutations occurring at the normal rate followed by multiple rounds of lineage selection and expansion (11)(12)(13)(14).These two hypotheses are not mutually exclusive. Indeed it is likely that carcinogenic pathways corresponding to both hypotheses contribute concurrently. For example, carcinogenesis could involve a mutator mutation and subsequent mutations augmented by lineage selection and expansion.The common outcome of a malignant lineage is likely approachable by numerous pathways, and we postulate that these pathways will be seen in clinical cancers in proportion to their relative efficiencies, irrespective of w...

Oncogenic phosphatase Wip1 is a novel prognostic marker for lung adenocarcinoma patient survival

“…Multiple studies showed that continuous formation of DNA double-strand breaks might contribute to increased genomic instability, leading to tumorigenesis, because of breach of a barrier (such as DNA damage response including p53 activation). (3,4,25,26) In this study, IHC staining of c-H2AX protein was carried out to detect presence of DNA damage in the tumor tissues and c-H2AX expression was observed in 38 of 84 samples (45.2%; Table 1). Interestingly, our result showed that increased expression of Wip1 was significantly associated with c-H2AX expression (P < 0.001).…”

Cancer cells and adaptive explanations

“…What the correlation does suggest, is that therapy will be a strong selection pressure, and that genetically heterogeneous tumours have better chances of getting through it. In any case, different strands of evidence suggest that the instability of cancer cells helps rather than hampers their evolution (see also Beckman and Loeb 2006). Although it is still unclear whether fidelity of heredity is ideal for evolution, we can safely consider it within the required range.…”

“…Hence natural selection was proposed to account for this: if the first hit is already advantageous for the cell, it will be spread through the population, making the combination of hits more likely by changing the background conditions on which the next hit will arise 16 . A related -and still very much debated -hypothesis is that of the "mutator phenotype" (Beckman and Loeb 2006;Loeb 1991), according to which one of the first hits increases genetic instability and thereby makes subsequent hits more likely. Once more, however, the CSC model provides an alternative explanation which is equally convincing: if cancer either arises in a stem cell or revert the cell to a pre-wired stem-cell state, the cell has the necessary lifespan.…”

Impact of genetic dynamics and single-cell heterogeneity on development of nonstandard personalized medicine strategies for cancer

“…Mathematical models using the focused quantitative modeling methodology (5) have demonstrated that genetic instability enhances the efficiency of carcinogenesis, a result that is robust across all plausible parameter values and model types (5)(6)(7). More efficient mechanisms of carcinogenesis should be more common in clinical tumors.…”