The role of whole genome doubling in cancer evolution

Martí Baena, Quim

The role of whole genome doubling in cancer evolution

Citation

Martí Baena, Q. The role of whole genome doubling in cancer evolution. 2021. handle: http://hdl.handle.net/10230/48225

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Abstract

Whole genome doubling (WGD) is one of the most common events in the early stages of cancer evolution. However, a consistent explanation for the pervasiveness of WGD across cancer types remains elusive. The duplication of the whole karyotype, produced by errors in cell division, is often followed by an increase in chromosomal instability (CIN) and intratumor heterogeneity, possibly allowing cancer cells to rapidly evolve and overcome selective barriers. This would explain why WGD has been associated with poor prognosis and multi-drug resistance along several cancer types, but it is not sucient to account for why WGD arises and is selected for even before the onset of CIN. In this work, a mathematical framework to model instability in the cancer genome is presented, inspired by early virus mutagenesis models. By considering the intertwined eects of ploidy and mutational rates in a simplied genome, the model is able to capture how the average chromosome number correlates with potential evolvability. This, in turn, might point towards WGD providing a buering eect to cancer cells that could allow the presence of the increased genome instability that is produced by CIN. In addition, our model indicates that increasing ploidy values does not allow tumors to explore much higher microsatellite instability levels, indicating that WGD might only be an evolutionary advantage in the presence of chromosomal instability. This result sheds light on the previously unresolved question of why WGD is an uncommon event in MMR-decient cancers.