Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution

López, Saioa; Lim, Emilia L.; Horswell, Stuart; Haase, Kerstin; Huebner, Ariana; Dietzen, Michelle; Mourikis, Thanos P.; Watkins, Thomas B.K.; Rowan, Andrew; Dewhurst, Sally M.; Birkbak, Nicolai J.; Wilson, Gareth A.; Loo, Peter Van; Jamal‐Hanjani, Mariam; Swanton, Charles; McGranahan, Nicholas

doi:10.1038/s41588-020-0584-7

Cited by 206 publications

(214 citation statements)

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“…Chromosomal-scale alterations are therefore expected to result in trade-offs between the dosages of positively- and negatively-selected elements 14 , potentially leading to stabilising selection on the aneuploid genome. Chromosomal changes may also have a buffering effect against deleterious point mutations 15 . Indeed, clinical studies show that the burden of CNAs is non-monotonically related with prognosis across cancer types 10 (first observed in breast cancer 16 ).…”

Section: Introductionmentioning

confidence: 99%

Negative selection may cause grossly altered but broadly stable karyotypes in metastatic colorectal cancer

Cross

Mossner

Nowinski

et al. 2020

Preprint

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Aneuploidy, defined as the loss and gain of whole and part chromosomes, is a near-ubiquitous feature of cancer genomes, is prognostic, and likely an important determinant of cancer cell biology. In colorectal cancer (CRC), aneuploidy is found in virtually all tumours, including precursor adenomas. However, the temporal evolutionary dynamics that select for aneuploidy remain broadly uncharacterised. Here we perform genomic analysis of 755 samples from a total of 167 patients with colorectal-derived neoplastic lesions that cross-sectionally represent the distinct stages of tumour evolution, and longitudinally track individual tumours through metastasis and treatment. Precancer lesions (adenomas) exhibited low levels of aneuploidy but high intra-tumour heterogeneity, whereas cancers had high aneuploidy but low heterogeneity, indicating that progression is through a genetic bottleneck that suppresses diversity. Individual CRC glands from the same tumour have similar karyotypes, despite prior evidence of ongoing instability at the cell level. Pseudo-stable aneuploid genomes were observed in metastatic lesions sampled from liver and other organs, after chemo- or targeted therapies, and late recurrences detected many years after the diagnosis of a primary tumour. Modelling indicates that these data are consistent with the action of stabilising selection that ‘traps’ cancer cell genomes on a fitness peak defined by the specific pattern of aneuploidy. These data show that the initial progression of CRC requires the traversal of a rugged fitness landscape and subsequent genomic evolution, including metastatic dissemination and therapeutic resistance, is constrained by stabilising selection.

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Section: Introductionmentioning

confidence: 99%

Negative selection may cause grossly altered but broadly stable karyotypes in metastatic colorectal cancer

Cross

Mossner

Nowinski

et al. 2020

Preprint

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“…It has been demonstrated that cells that have experienced a WGD event (hereafter WGD + ) are oncogenic and can facilitate tumorigenesis 4,5 . WGD promotes tumorigenesis in at least two ways: first, proliferating WGD + cells are genomically unstable and rapidly accumulate both numerical and structural chromosomal abnormalities 5 , and second, WGD + cells are better able to buffer against the negative effects of deleterious mutations and ongoing chromosome instability 6-10 . Such traits enable nascent WGD + tumor cells to proliferate in the presence of otherwise lethal genomic alterations while simultaneously sampling increased genetic permutations, ultimately enabling phenotypic leaps that give rise to tumors 8,11 .…”

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confidence: 99%

Whole genome doubling confers unique genetic vulnerabilities on tumor cells

Quinton

DiDomizio

Vittoria

et al. 2020

Preprint

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47Whole genome doubling (WGD) occurs early in tumorigenesis and generates genetically 48 unstable tetraploid cells that fuel tumor development. Cells that undergo WGD (WGD + ) 49 must adapt to accommodate their abnormal tetraploid state; however, the nature of these 50 adaptations, and whether they confer vulnerabilities that can subsequently be exploited 51 therapeutically, is unclear. Using sequencing data from ~10,000 primary human cancer 52 samples and essentiality data from ~600 cancer cell lines, we show that WGD gives rise to 53 common genetic traits that are accompanied by unique vulnerabilities. We reveal that 54 WGD + cells are more dependent on spindle assembly checkpoint signaling, DNA 55 replication factors, and proteasome function than WGDcells. We also identify KIF18A, 56 which encodes for a mitotic kinesin, as being specifically required for the viability of 57 WGD + cells. While loss of KIF18A is largely dispensable for accurate chromosome 58 segregation during mitosis in WGDcells, its loss induces dramatic mitotic errors in 59 WGD + cells, ultimately impairing cell viability. Collectively, our results reveal new 60 strategies to specifically target WGD + cancer cells while sparing the normal, non-61 transformed WGDcells that comprise human tissue. 62The vast majority of human cells are diploid and numerous cell cycle controls exist to help 63 ensure that this state is maintained across successive cell divisions 1 . Despite these controls, 64 errors can occur that result in a whole genome doubling (WGD), in which a natively diploid cell 65 transitions to a tetraploid state 1-3 . It has been demonstrated that cells that have experienced a 66 WGD event (hereafter WGD + ) are oncogenic and can facilitate tumorigenesis 4,5 . WGD promotes 67 tumorigenesis in at least two ways: first, proliferating WGD + cells are genomically unstable and 68 rapidly accumulate both numerical and structural chromosomal abnormalities 5 , and second, 69 WGD + cells are better able to buffer against the negative effects of deleterious mutations and 70 ongoing chromosome instability 6-10 . Such traits enable nascent WGD + tumor cells to proliferate 71 in the presence of otherwise lethal genomic alterations while simultaneously sampling increased 72 genetic permutations, ultimately enabling phenotypic leaps that give rise to tumors 8,11 . WGD also 73 carries important clinical implications, with recent reports showing its correlation with advanced 74 metastatic disease and a worse overall prognosis 12,13 . 75 76 Given the oncogenic potential associated with WGD, tumor suppression mechanisms exist to limit 77 the proliferation of these unstable cells. WGD + cells activate both the p53 and Hippo tumor 78 suppressor pathways and are prone to apoptosis, senescence, and immune clearance [14][15][16] . WGD also 79gives rise to numerous abnormalities in cellular physiology that impair fitness 6,14,17 . Therefore, in 80 order to promote tumorigenesis, WGD + cells must adapt to overcome these barriers 5,14,18,19 . Thus, 81 while ...

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“…A next step will be to extend our model to include mutation events, specifically chromosome mis-segregations that contribute extensively to diversify ploidy of a population [31,32]. The additional DNA content of high-ploidy cells, though energetically costly, brings a masking effect against the deleterious consequences of chromosome losses [22]. This duality may explain the higher sensitivity to glycolysis inhibitors of high-ploidy cells and their lower sensitivity to cytotoxic drugs previously reported in Glioblastoma [57].…”

Section: Discussionmentioning

confidence: 98%

“…All these energetic contingencies determine whether phenotypic differences between goers and growers manifest as such, and explain why non-proliferative arrested cells can have the same motility as cycling cells [30]. A future extension will be to integrate our model of the potential cost of high ploidy with existing Markov models of the robustness benefits it can provide against deleterious mutations [22,31,32]. With a better understanding of the nature of the double-edged sword of high ploidy, we aim to contribute towards personalized combination-therapies with cytotoxic drugs and inhibitors of signal transduction pathways such as MTOR-Is.…”

Section: Overall Model Designmentioning

confidence: 99%

“…Multiple studies have described a minority population of PACCS with an unusual resilience to stress [19][20][21]. A very recent investigation of evolutionary selection pressures for WGD suggests that it mitigates the accumulation of deleterious somatic alterations [22]. However, it is not clear what costs cells with a duplicated genome pay for this robustness.…”

Section: Introductionmentioning

confidence: 99%

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Invasion of homogeneous and polyploid populations in nutrient-limiting environments

Kimmel

Dane

Heiser

et al. 2020

Preprint

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Breast cancer progresses in a multistep process from primary tumor growth and stroma invasion to metastasis. Progression is accompanied by a switch to an invasive cell phenotype. Nutrient-limiting environments exhibit chemotaxis with aggressive morphologies characteristic of invasion. The mTOR pathway senses essential nutrients, informing the cell to respond with either increased chemotaxis and nutrient uptake or cell cycle progression. Randomized clinical trials have shown that mTOR inhibitors (mTOR-I) improve the outcome of metastatic breast cancer patients. However, there are considerable differences between and within tumors that impact the effectiveness of mTOR-I, including differences in access to nutrients. It is unknown how co-existing cells differ in their response to nutrient limitations and how this impacts invasion of the metapopulation as a whole. We integrate modeling with microenvironmental perturbations data to investigate invasion in nutrient-limiting environments inhabited by one or two cancer cell subpopulations. Hereby subpopulations are defined by their energy efficiency and chemotactic ability. We calculate the invasion-distance traveled by a homogeneous population. For heterogeneous populations, our results suggest that an imbalance between nutrient efficacy and chemotactic superiority accelerates invasion. Such imbalance will segregate the two populations spatially and only one type will dominate at the invasion front. Only if these two phenotypes are balanced do the two populations compete for the same space, which decelerates invasion. We investigate ploidy as a candidate biomarker of this phenotypic heterogeneity to discern circumstances when inhibiting chemotaxis amplifies innternal competition and decelerates tumor progression, from circumstances that render clinical consequences of chemotactic inhibition unfavorable. Significance: A better understanding of the nature of the double-edged sword of high ploidy is a prerequisite to personalize combinationtherapies with cytotoxic drugs and inhibitors of signal transduction pathways such as MTOR-Is.

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Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution

Cited by 206 publications

References 50 publications

Negative selection may cause grossly altered but broadly stable karyotypes in metastatic colorectal cancer

Negative selection may cause grossly altered but broadly stable karyotypes in metastatic colorectal cancer

Whole genome doubling confers unique genetic vulnerabilities on tumor cells

Invasion of homogeneous and polyploid populations in nutrient-limiting environments

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