Evidence map›Paper›PMID 28177473›Full record

ArticleAnnals of oncology : official journal of the European Society for Medical Oncology2017

Cyclin D mediates tolerance of genome-doubling in cancers with functional p53.

A Crockford, L P Zalmas, E Grönroos, S M Dewhurst, N McGranahan, M E Cuomo, V Encheva, A P Snijders, J Begum, S Purewal and 4 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Annals of oncology : official journal of the European Society for Medical Oncology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.

0numbers the graph read from it
0cells of the map it votes in
35citing papers in PubMed
2.8field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

35 citing papers in PubMed, 50 citations in OpenAlex.

  1. Article
  2. Article
  3. Review
  4. Article
  5. Review
  6. Article
  7. Review
  8. Article
  9. Surviving the Storm: The Role of Poly- and Depolyploidization in Tissues and Tumors.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024
    Review
  10. The TP53-activated E3 ligase RNF144B is a tumour suppressor that prevents genomic instability.Journal of experimental & clinical cancer research : CR · 2024
    Article
  11. Review
  12. Article
  13. Whole-genome doubling in tissues and tumors.Trends in genetics : TIG · 2023
    Review
  14. Article
  15. Permission to pass: on the role of p53 as a gatekeeper for aneuploidy.Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology · 2023
    Review
  16. Review
  17. Article
  18. Article
  19. Article
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 1 institution in 1 country.

A CrockfordTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
L P ZalmasTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
E GrönroosTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
S M DewhurstTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
N McGranahanTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
M E CuomoTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
V EnchevaTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
A P SnijdersTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
J BegumTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
S PurewalTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
J CerveiraTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
H PatelTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
M J RenshawTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
C SwantonTranslational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.
The Francis Crick Institute · GB

Funding

Wellcome Trust FC001169
6 · The paper itself

Abstract

Background: Aneuploidy and chromosomal instability (CIN) are common features of human malignancy that fuel genetic heterogeneity. Although tolerance to tetraploidization, an intermediate state that further exacerbates CIN, is frequently mediated by TP53 dysfunction, we find that some genome-doubled tumours retain wild-type TP53. We sought to understand how tetraploid cells with a functional p53/p21-axis tolerate genome-doubling events. Methods: We performed quantitative proteomics in a diploid/tetraploid pair within a system of multiple independently derived TP53 wild-type tetraploid clones arising spontaneously from a diploid progenitor. We characterized adapted and acute tetraploidization in a variety of flow cytometry and biochemical assays and tested our findings against human tumours through bioinformatics analysis of the TCGA dataset. Results: Cyclin D1 was found to be specifically overexpressed in early but not late passage tetraploid clones, and this overexpression was sufficient to promote tolerance to spontaneous and pharmacologically induced tetraploidy. We provide evidence that this role extends to D-type cyclins and their overexpression confers specific proliferative advantage to tetraploid cells. We demonstrate that tetraploid clones exhibit elevated levels of functional p53 and p21 but override the p53/p21 checkpoint by elevated expression of cyclin D1, via a stoichiometry-dependent and CDK activity-independent mechanism. Tetraploid cells do not exhibit increased sensitivity to abemaciclib, suggesting that cyclin D-overexpressing tumours might not be specifically amenable to treatment with CDK4/6 inhibitors. Conclusions: Our study suggests that D-type cyclin overexpression is an acute event, permissive for rapid adaptation to a genome-doubled state in TP53 wild-type tumours and that its overexpression is dispensable in later stages of tumour progression.

Indexed as

AdenocarcinomaAminopyridinesBenzimidazolesCell Line, TumorColorectal NeoplasmsCyclin CCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Cyclin-Dependent Kinase Inhibitor p21Cytochalasin BDiploidyFlow CytometryGene Knockdown TechniquesGenes, p53HCT116 CellsHumansabemaciclibAminopyridinesBenzimidazolesCCNC protein, humanCDK4 protein, humanCDK6 protein, humanCDKN1A protein, humanCyclin CCyclin-Dependent Kinase 4Cyclin-Dependent Kinase 6Cyclin-Dependent Kinase Inhibitor p21Cytochalasin Bdihydrocytochalasin BProtein Kinase InhibitorsTP53 protein, humanTumor Suppressor Protein p53

Identifiers

PMID28177473
PMCPMC5391719
OpenAlexW2551833433

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.