A deterministic model for the occurrence and dynamics of multiple mutations in hierarchically organized tissues

We model a general, hierarchically organized tissue by a multi compartment approach, allowing any number of mutations within a cell. We derive closed solutions for the deterministic clonal dynamics and the reproductive capacity of single clones. Our results hold for the average dynamics in a hierarchical tissue characterized by an arbitrary combination of proliferation parameters.Comment: 4 figures, to appear in Royal Society Interfac

Should tissue structure suppress or amplify selection to minimize cancer risk?

It has been frequently argued that tissues evolved to suppress the accumulation of growth enhancing cancer inducing mutations. A prominent example is the hierarchical structure of tissues with high cell turnover, where a small number of tissue specific stem cells produces a large number of specialized progeny during multiple differentiation steps. Another well known mechanism is the spatial organization of stem cell populations and it is thought that this organization suppresses fitness enhancing mutations. However, in small populations the suppression of advantageous mutations typically also implies an increased accumulation of deleterious mutations. Thus, it becomes an important question whether the suppression of potentially few advantageous mutations outweighs the combined effects of many deleterious mutations

How many samples are needed to infer truly clonal mutations from heterogenous tumours?

BACKGROUND: Modern cancer treatment strategies aim to target tumour specific genetic (or epigenetic) alterations. Treatment response improves if these alterations are clonal, i.e. present in all cancer cells within tumours. However, the identification of truly clonal alterations is impaired by the tremendous intra-tumour genetic heterogeneity and unavoidable sampling biases. METHODS: Here, we investigate the underlying causes of these spatial sampling biases and how the distribution and sizes of biopsies in sampling protocols can be optimised to minimize such biases. RESULTS: We find that in the ideal case, less than a handful of samples can be enough to infer truly clonal mutations. The frequency of the largest sub-clone at diagnosis is the main factor determining the accuracy of truncal mutation estimation in structured tumours. If the first sub-clone is dominating the tumour, higher spatial dispersion of samples and larger sample size can increase the accuracy of the estimation. In such an improved sampling scheme, fewer samples will enable the detection of truly clonal alterations with the same probability. CONCLUSIONS: Taking spatial tumour structure into account will decrease the probability to misclassify a sub-clonal mutation as clonal and promises better informed treatment decisions

Reply: Evolutionary game theory: lessons and limitations, a cancer perspective

SCOPUS: le.jinfo:eu-repo/semantics/publishe

Cancer phenotype as the outcome of an evolutionary game between normal and malignant cells

There is variability in the cancer phenotype across individuals: two patients with the same tumour may experience different disease life histories, resulting from genetic variation within the tumour and from the interaction between tumour and host. Until now, phenotypic variability has precluded a clear-cut identification of the fundamental characteristics of a given tumour type.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

On the dynamics of neutral mutations in a mathematical model for a homogeneous stem cell population

The theory of the clonal origin of cancer states that a tumour arises from one cell that acquires mutation(s) leading to the malignant phenotype. It is the current belief that many of these mutations give a fitness advantage to the mutant population allowing it to expand, eventually leading to disease. However,mutations that lead to such a clonal expansion need not give a fitness advantage and may in fact be neutral—or almost neutral—with respect to fitness. Such mutant clones can be eliminated or expand stochastically, leading to a malignant phenotype (disease). Mutations in haematopoietic stem cells give rise to diseases such as chronic myeloid leukaemia (CML) and paroxysmal nocturnal haemoglobinuria (PNH). Although neutral drift often leads to clonal extinction, disease is still possible, and in this case, it has important implications both for the incidence of disease and for therapy, as it may be more difficult to eliminate neutral mutations with therapy. We illustrate the consequences of such dynamics, using CML and PNH as examples. These considerations have implications for many other tumours as well

Eml1 loss impairs apical progenitor spindle length and soma shape in the developing cerebral cortex

The ventricular zone (VZ) of the developing cerebral cortex is a pseudostratified epithelium that contains progenitors undergoing precisely regulated divisions at its most apical side, the ventricular lining (VL). Mitotic perturbations can contribute to pathological mechanisms leading to cortical malformations. The HeCo mutant mouse exhibits subcortical band heterotopia (SBH), likely to be initiated by progenitor delamination from the VZ early during corticogenesis. The causes for this are however, currently unknown. Eml1, a microtubule (MT)-associated protein of the EMAP family, is impaired in these mice. We first show that MT dynamics are perturbed in mutant progenitor cells in vitro. These may influence interphase and mitotic MT mechanisms and indeed, centrosome and primary cilia were altered and spindles were found to be abnormally long in HeCo progenitors. Consistently, MT and spindle length regulators were identified in EML1 pulldowns from embryonic brain extracts. Finally, we found that mitotic cell shape is also abnormal in the mutant VZ. These previously unidentified VZ characteristics suggest altered cell constraints which may contribute to cell delamination