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

Jarno Drost, Ruben van Boxtel, Francis Blokzijl, Tomohiro Mizutani, Nobuo Sasaki, Valentina Sasselli, Joep de Ligt, Sam Behjati, Judith E Grolleman, Tom van Wezel, Serena Nik-Zainal, Roland P Kuiper, Edwin Cuppen, Hans Clevers

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Mutational processes underlie cancer initiation and progression. Signatures of these processes in cancer genomes may explain cancer etiology and could hold diagnostic and prognostic value. We developed a strategy that can be used to explore the origin of cancer-associated mutational signatures. We used CRISPR-Cas9 technology to delete key DNA repair genes in human colon organoids, followed by delayed subcloning and whole-genome sequencing. We found that mutation accumulation in organoids deficient in the mismatch repair gene MLH1 is driven by replication errors and accurately models the mutation profiles observed in mismatch repair-deficient colorectal cancers. Application of this strategy to the cancer predisposition gene NTHL1, which encodes a base excision repair protein, revealed a mutational footprint (signature 30) previously observed in a breast cancer cohort. We show that signature 30 can arise from germline NTHL1 mutations.

Original languageEnglish
Pages (from-to)234-238
Number of pages5
JournalScience
Volume358
Issue number6360
DOIs
Publication statusPublished - 13 Oct 2017

Keywords

  • Journal Article
  • Research Support, Non-U.S. Gov't

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