Use of CRISPR-modified human stem cell organoids to study the origin of mutational signatures in cancer-Reference-Cited by-同舟云学术

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

Published:2017-10-13 Issue:6360 Volume:358 Page:234-238
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Drost Jarno¹²^ORCID,van Boxtel Ruben²³^ORCID,Blokzijl Francis²³^ORCID,Mizutani Tomohiro¹²^ORCID,Sasaki Nobuo¹²^ORCID,Sasselli Valentina¹²^ORCID,de Ligt Joep²³^ORCID,Behjati Sam⁴⁵^ORCID,Grolleman Judith E.⁶^ORCID,van Wezel Tom⁷^ORCID,Nik-Zainal Serena⁴⁸^ORCID,Kuiper Roland P.⁶⁹^ORCID,Cuppen Edwin²³^ORCID,Clevers Hans¹²⁹^ORCID

Affiliation:

1. Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center (UMC) Utrecht, 3584CT Utrecht, Netherlands.

2. Cancer Genomics Netherlands, UMC Utrecht, 3584CX Utrecht, Netherlands.

3. Center for Molecular Medicine, Department of Genetics, UMC Utrecht, 3584CX Utrecht, Netherlands.

4. Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK.

5. Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK.

6. Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

7. Departments of Pathology, Leiden University Medical Center, Leiden, Netherlands.

8. East Anglian Medical Genetics Service, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK.

9. Princess Máxima Center for Pediatric Oncology, 3584CT Utrecht, Netherlands.

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

Funder

Wellcome Trust

Cancer Genomics Centre

Stand Up To Cancer

Worldwide Cancer Research

St Baldrick’s Foundation

Netherlands Organization for Scientific Research

KWF Kankerbestrijding

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary