CoChat
Sign Up
Cited by 461Cancer Genomics and DiagnosticsDNA Repair MechanismsGenetic factors in colorectal cancer

Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer

Open access
Drost, Jarno, van Boxtel, Ruben, Blokzijl, Francis, Mizutani, Tomohiro, Sasaki, Nobuo, Sasselli, Valentina, de Ligt, Joep, Behjati, Sam +6 more·2017·Science
DOI 10.1126/science.aao3130PMC PMC6038908
Open this paper in CoChat — free account

Abstract

A signature event for organoids: Human cancer genomes harbor cryptic mutational signatures that represent the cumulative effects of DNA damage and defects in DNA repair processes. Knowledge of how specific signatures originate could have a major impact on cancer diagnosis and prevention. One approach to address this question is to reproduce the signatures in experimental systems by genetic engineering and then match the signatures to those found in naturally occurring cancers. Drost et al. used CRISPR-Cas9 to delete certain DNA repair enzymes from human colon organoids. In a proof-of-concept study, they show that deficiency in base excision repair is responsible for a mutational signature previously identified in cancer genome sequencing projects. Science , this issue p. 234

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1126/science.aao3130

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Several preclinical human transformation organoid models have been developed through sequential CRISPR modifications of single or multiple oncogenic loci.

    “Several preclinical human transformation organoid models have been developed through sequential CRISPR modifications of single or multiple oncogenic loci9–13.”

    From Large-scale CRISPR screening in primary human 3D gastric organoids enables comprehensive dissection of gene-drug interactions (2025) · cites this paper as [10]

    The paper’s Abstract describes CRISPR-edited human colon organoids used to model cancer-associated mutational signatures. It describes deleting DNA-repair genes, not sequentially modifying oncogenic loci to create transformation models; that more specific part of the claim is unsupported. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 37 · Cited by 461

Research works printed but not linked: 29

  1. [1]Alexandrov LB Nature 2013 500 415 421 23945592 PMC3776390
  2. [2]Davies H Nat Med 2017 23 517 525 28288110 PMC5833945
  3. [3]Alexandrov LB Science 2016 354 618 622 27811275 PMC6141049
  4. [4]Behjati S Nat Commun 2016 7 12605 27615322 PMC5027243
  5. [5]Kim J Nat Genet 2016 48 600 606 27111033 PMC4936490
  6. [6]Huch M Cell 2015 160 299 312 25533785 PMC4313365
  7. [7]Blokzijl F Nature 2016 538 260 264 27698416 PMC5536223
  8. [8]Behjati S Nature 2014 513 422 425 25043003 PMC4227286
  9. [9]Drost J Nature 2015 521 43 47 25924068
  10. [10]MacRae SL Aging 2015 7 1171 1182 26729707 PMC4712340
  11. [11]Parrinello S Nat Cell Biol 2003 5 741 747 12855956 PMC4940195
  12. [12]Lynch HT de la Chapelle A N Engl J Med 2003 348 919 932 12621137
  13. [13]Lynch HT Snyder CL Shaw TG Heinen CD Hitchins MP Nat Rev Cancer 2015 15 181 194 25673086
  14. [14]Barker N Nature 2009 457 608 611 19092804
  15. [15]Peltomäki P Hum Mol Genet 2001 10 735 740 11257106
  16. [16]Schuster-Böckler B Lehner B Nature 2012 488 504 507 22820252
  17. [17]Supek F Lehner B Nature 2015 521 81 84 25707793 PMC4425546
  18. [18]Zheng CL Cell Rep 2014 9 1228 1234 25456125 PMC4254608
  19. [19]Hansen RS Proc Natl Acad Sci USA 2010 107 139 144 19966280 PMC2806781
  20. [20]Jiricny J Nat Rev Mol Cell Biol 2006 7 335 346 16612326
  21. [21]Haradhvala NJ Cell 2016 164 538 549 26806129 PMC4753048
  22. [22]Tomasetti C Li L Vogelstein B Science 2017 355 1330 1334 28336671 PMC5852673
  23. [23]Alexandrov LB Nik-Zainal S Wedge DC Campbell PJ Stratton MR Cell Rep 2013 3 246 259 23318258 PMC3588146
  24. [24]Viel A EBioMedicine 2017 20 39 49 28551381 PMC5478212
  25. [25]Prasad A Wallace SS Pederson DS Mol Cell Biol 2007 27 8442 8453 17923696 PMC2169407
  26. [26]Li J Braganza A Sobol RW Antioxid Redox Signal 2013 18 2429 2443 23311711 PMC3671628
  27. [27]Weren RD Nat Genet 2015 47 668 671 25938944
  28. [28]Rivera B Castellsagué E Bah I van Kempen LC Foulkes WD N Engl J Med 2015 373 1985 1986 26559593
  29. [29]Nik-Zainal S Nature 2016 534 47 54 27135926 PMC4910866

Authors
Drost, J., van Boxtel, R., Blokzijl, F., Mizutani, T., Sasaki, N., Sasselli, V., de Ligt, J., Behjati, S., Grolleman, J. E., van Wezel, T., Nik-Zainal, S., Kuiper, R. P., Cuppen, E., & Clevers, H.
Affiliations
  • Royal Netherlands Academy of Arts and Sciences (NL)
  • Cancer Genomics Netherlands, UMC Utrecht, 3584CX Utrecht, Netherlands.
  • University Medical Center Utrecht (NL)
  • University of Cambridge (GB)
  • Radboud University Medical Center (NL)
  • Departments of Pathology, Leiden University Medical Center, Leiden, Netherlands.
  • Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.
Corresponding author
  • Drost, Jarno
  • Cuppen, Edwin
  • Clevers, Hans
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2017-10-13
Volume
358
Issue
6360
Pages
234-238
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.aao3130
PMC
PMC6038908
OpenAlex
W2755775794
Cited by
461
References
37
Citations by year
2026: 31 · 2025: 49 · 2024: 42 · 2023: 45 · 2022: 51 · 2021: 73 · 2020: 66 · 2019: 53 · 2018: 46 · 2017: 5
FWCI
15.60
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Leiden Repository (Leiden University) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion)
  • Apollo
Funders
  • Wellcome Trust (award337996)
  • Cancer Genomics Centre (award337998, award345340)
  • Stand Up To Cancer (award345289, award345290)
  • Worldwide Cancer Research (award337995, 16-0193)
  • St Baldrick’s Foundation (award337997)
  • Netherlands Organization for Scientific Research (award337994, 91614138)
  • KWF Kankerbestrijding (award346786, KUN2014-7209)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Keywords
mutational signatures, CRISPR/Cas9, colon organoids, base excision repair, DNA repair deficiency, DNA damage, cancer genomics
MeSH terms
MutL Protein Homolog 1, Breast Neoplasms, Colon, DNA Repair, DNA Replication, Female, Humans, Neoplasms, Organoids, Stem Cells, Colorectal Neoplasms, Mutagenesis, Germ-Line Mutation, Deoxyribonuclease (Pyrimidine Dimer), DNA Mismatch Repair, INDEL Mutation, CRISPR-Cas Systems

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review