Widespread Selection for Oncogenic Mutant Allele Imbalance in Cancer

Bielski, Craig M.; Donoghue, Mark T.A.; Gadiya, Mayur; Hanrahan, Aphrothiti J.; Won, Helen; Chang, Matthew T.; Jonsson, Philip; Penson, A.; Gorelick, Alexander N.; Harris, Christopher; Schram, Alison M.; Syed, Aijazuddin; Zehir, Ahmet; Chapman, Paul B.; Hyman, David M.; Solit, David B.; Shannon, Kevin; Chandarlapaty, Sarat; Berger, Michael F.; Taylor, Barry S.

doi:10.1016/j.ccell.2018.10.003

Cited by 80 publications

(95 citation statements)

References 45 publications

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“…Evidence for a possible dosage dependency of genetic PI3K pathway activation in cancer, including for PIK3CA mutation [12,13], has recently re-emerged [14]. This is in line with other studies showing pervasive selection in cancer for oncogenic mutant allele imbalance [15,16].…”

Section: Class I Pi3ks -Pik3ca Mutation and Amplificationsupporting

confidence: 76%

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

Vanhaesebroeck

Bilanges

Madsen

et al. 2019

Preprint

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Genetic activation of the class I PI3K pathway is very common in cancer. This mostly results from oncogenic mutations in PIK3CA, the gene encoding the ubiquitously expressed PI3Kα catalytic subunit, or from inactivation of the PTEN tumour suppressor, a lipid phosphatase which opposes class I PI3K signalling. The clinical impact of PI3K inhibitors in solid tumours, aimed at dampening cancercell-intrinsic PI3K activity, has thus far been limited. Challenges include poor drug tolerance, incomplete pathway inhibition and pre-existing or inhibitor-induced resistance. The principle of pharmacologically targeting cancer-cell-intrinsic PI3K activity also assumes that all cancer-promoting effects of PI3K activation are reversible, which might not be the case. Emerging evidence suggests that genetic PI3K pathway activation can induce and/or allow cells to tolerate chromosomal instability, which -even if occurring in a low fraction of the cell population -might help to facilitate and/or drive tumour evolution. While it is clear that such genomic events cannot be reverted pharmacologically, a role for PI3K in the regulation of chromosomal instability could be exploited by using PI3K pathway inhibitors to prevent those genomic events from happening and/or reduce the pace at which they are occurring, thereby dampening cancer development or progression. Such an impact might be most effective in tumours with clonal PI3K activation and achievable at lower drug doses than the maximum-tolerated doses of PI3K inhibitors currently used in the clinic.

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Section: Class I Pi3ks -Pik3ca Mutation and Amplificationsupporting

confidence: 76%

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

Vanhaesebroeck

Bilanges

Madsen

et al. 2019

Preprint

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“…Across all cancers, the signal of positive selection was more pronounced for clonal mutations (Figures 4b-e), with the highest dN/dS values found in amplified mutations 38 . Subclonal mutations on the other hand demonstrated much lower dN/dS values.…”

Section: Resultsmentioning

confidence: 99%

Measuring the distribution of fitness effects in somatic evolution by combining clonal dynamics with dN/dS ratios

Williams

Zapata

Werner

et al. 2019

Preprint

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15The distribution of fitness effects (DFE) defines how new mutations spread through an 16 evolving population. The ratio of non-synonymous to synonymous mutations (dN/dS) has 17 become a popular method to detect selection in somatic cells, however the link, in somatic 18 evolution, between dN/dS values and fitness coefficients is missing. Here we present a 19 quantitative model of somatic evolutionary dynamics that yields the selective coefficients 20 from individual driver mutations from dN/dS estimates, and then measure the DFE for 21 somatic mutant clones in ostensibly normal oesophagus and skin. We reveal a broad 22 distribution of fitness effects, with the largest fitness increases found for TP53 and NOTCH1 23 mutants (proliferative bias 1-5%). Accurate measurement of the per-gene DFE in cancer 24 evolution is precluded by the quality of currently available sequencing data. This study 25provides the theoretical link between dN/dS values and selective coefficients in somatic 26 evolution, and reveals the DFE for mutations in human tissues. 27 28 29Introduction 30 31One of the principal goals of large-scale somatic genome sequencing is to uncover genetic loci 32 under positive selection, so-called "driver" genes, that lead to clonal expansions. 33Enumeration of the selective advantage of each driver mutation enables prediction of future 34 evolutionary dynamics 1 . In evolutionary biology, the distribution of fitness effects (DFE) is a 35 fundamental entity that describes the selective consequences of a (large) number of 36 individual mutations of an ancestral genome 2 . In somatic evolution, particularly cancer 37 genomes, we have an extensive knowledge of the catalogue of recurrent, and likely positively 38 selected, somatic mutations 3 , but the fitness changes associated with each mutation remain 39 largely unquantified. 40 41Extensive experimental effort is ongoing to determine the fitness effects of mutations. Most 42 prominently is lineage tracing of mutations in mouse models 4,5 , but these methods are not 43 sufficiently high-throughput to produce the DFE for all somatic mutations. Other studies have 44 estimated the selective coefficient of somatic mutations by measuring the frequency of such 45 mutations over time in the same individual using longitudinal sampling 6,7 however this 46 method is broadly limited to somatic evolution in the blood (where it is feasible to take 47

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“…U2AF1 was recently identified as a haplo-essential cancer gene based on computational analysis of sequencing data. Unlike other oncogenic driver gene mutations that undergo allelic imbalance (e.g., copy number alteration [amplification or deletion] or uniparental disomy) to increase the mutant allele dosage over the wild-type allele, spliceosome gene mutations undergo negative selection to preserve and skew towards the wild-type allele when an allelic imbalance occurs in a tumor (12). Our results show that hemizygous (i.e., one mutant and one deleted allele) hematopoietic cells are not viable and have a strong competitive disadvantage in competitive repopulation assays compared to wild-type cells, confirming that the wild-type allele is required for viability, and consistent with U2AF1 being a haplo-essential cancer gene.…”

Section: Discussionmentioning

confidence: 99%

“…U2AF1 mutations are always heterozygous with the residual wild-type allele expressed, suggesting that mutant hematopoietic cells may require one copy of wild-type U2AF1 for survival. Consistent with this, U2AF1 has been nominated as a haplo-essential cancer gene (e.g., cancer cells with a U2AF1 heterozygous mutation are under selective pressure to maintain at least one copy of the U2AF1 wild-type allele) based on analysis of large-scale sequencing studies (12).…”

Section: Introductionmentioning

confidence: 94%

U2AF1is a haplo-essential gene required for cancer cell survival

Wadugu

Heard

Srivatsan

et al. 2020

Preprint

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Somatic mutations in the spliceosome gene U2AF1 are common in patients with myelodysplastic syndromes. U2AF1 mutations that code for the most common amino acid substitutions are always heterozygous, and the retained wild-type allele is expressed, suggesting that mutant hematopoietic cells may require the residual wild-type allele to be viable and cause disease. We show that hematopoiesis and RNA splicing in U2af1 heterozygous knock-out mice was similar to control mice, but that deletion of the wild-type allele in U2AF1(S34F) heterozygous mutant expressing hematopoietic cells (i.e., hemizygous mutant) was lethal. These results confirm that U2AF1 mutant hematopoietic cells are dependent on the expression of wild-type U2AF1 for survival in vivo and that U2AF1 is a haplo-essential cancer gene. Mutant U2AF1 (S34F) expressing cells were also more sensitive to reduced, but not absent, expression of wild-type U2AF1 than non-mutant cells. Furthermore, mice transplanted with leukemia cells expressing mutant U2AF1 had significantly reduced tumor burden and improved survival after the wild-type U2af1 allele was deleted compared to when it was not deleted. These results suggest that selectively targeting the wild-type U2AF1 allele in heterozygous mutant cells could induce cancer cell death and be a therapeutic strategy for patients harboring U2AF1 mutations.

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Widespread Selection for Oncogenic Mutant Allele Imbalance in Cancer

Cited by 80 publications

References 45 publications

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

Perspective: Potential Impact and Therapeutic Implications of Oncogenic PI3K Activation on Chromosomal Instability

Measuring the distribution of fitness effects in somatic evolution by combining clonal dynamics with dN/dS ratios

U2AF1is a haplo-essential gene required for cancer cell survival

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