Elevated Tolerance to Aneuploidy in Cancer Cells: Estimating the Fitness Effects of Chromosome Number Alterations by In Silico Modelling of Somatic Genome Evolution

Anders Valind,David Gisselsson,Yuesheng Jin,Daniela Cimini

doi:10.1371/journal.pone.0070445

Abstract

An unbalanced chromosome number (aneuploidy) is present in most malignant tumours and has been attributed to mitotic mis-segregation of chromosomes. However, recent studies have shown a relatively high rate of chromosomal mis-segregation also in non-neoplastic human cells, while the frequency of aneuploid cells remains low throughout life in most normal tissues. This implies that newly formed aneuploid cells are subject to negative selection in healthy tissues and that attenuation of this selection could contribute to aneuploidy in cancer. To test this, we modelled cellular growth as discrete time branching processes, during which chromosome gains and losses were generated and their host cells subjected to selection pressures of various magnitudes. We then assessed experimentally the frequency of chromosomal mis-segregation as well as the prevalence of aneuploid cells in human non-neoplastic cells and in cancer cells. Integrating these data into our models allowed estimation of the fitness reduction resulting from a single chromosome copy number change to an average of ≈30% in normal cells. In comparison, cancer cells showed an average fitness reduction of only 6% (p = 0.0008), indicative of aneuploidy tolerance. Simulations based on the combined presence of chromosomal mis-segregation and aneuploidy tolerance reproduced distributions of chromosome aberrations in >400 cancer cases with higher fidelity than models based on chromosomal mis-segregation alone. Reverse engineering of aneuploid cancer cell development in silico predicted that aneuploidy intolerance is a stronger limiting factor for clonal expansion of aneuploid cells than chromosomal mis-segregation rate. In conclusion, our findings indicate that not only an elevated chromosomal mis-segregation rate, but also a generalised tolerance to novel chromosomal imbalances contribute to the genomic landscape of human tumours.

Highlights

Over the last decade, a number of molecular mechanisms causing genomic alterations in cancer cells have been described
The present study provides evidence from multiple human cell systems, including primary cells, that a certain degree of aneuploidy intolerance exists in non-neoplastic human cells, and that this intolerance can be attenuated in cancer to allow longterm clonal expansion of cells with an elevated chromosomal missegregation rate
It thereby corroborates previous scarce investigations suggesting that specific aneuploidy tolerance mechanisms exist in human cells [14,34]

Summary

Introduction

A number of molecular mechanisms causing genomic alterations in cancer cells have been described. It has been shown that chromosomes that missegregate can be damaged during cytokinesis, leading to DNA double strand breaks and unbalanced translocations in the daughter cells, implying an overlap between the routes leading to numerical and structural aberrations [7]. A prerequisite for the establishment of complex structural chromosome aberrations is tolerance to DNA double strand breaks, most inactivation of the p53-dependent response [1,8]. A tolerance to DNA breaks appears to be a very common feature in tumour cells when compared to non-neoplastic cells, allowing the mechanisms giving rise to genomic alterations to become established in tumours and enhancing the probability for tumorigenic mutations to occur [9]

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