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

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

in Base excision repair / Breast cancer / Breast Neoplasms - genetics / Cancer / Colon / Colorectal cancer / Colorectal Neoplasms - genetics / CRISPR / CRISPR-Cas Systems / Deoxyribonuclease (Pyrimidine Dimer) - genetics / Deoxyribonucleic acid / DNA / DNA damage / DNA Mismatch Repair - genetics / DNA repair / DNA Repair - genetics / DNA Replication / Etiology / Female / Gene sequencing / Genetic engineering / Genomes / Germ-Line Mutation / Humans / INDEL Mutation / Knowledge management / Mismatch repair / MLH1 protein / Mutagenesis / Mutation / MutL Protein Homolog 1 - genetics / Neoplasms - genetics / Organoids / Signatures / Stem Cells

2017

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

2017

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

2017

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Journal Article

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

Clevers, Hans,

van Wezel, Tom,

van Boxtel, Ruben,

Sasselli, Valentina,

de Ligt, Joep,

Sasaki, Nobuo,

Kuiper, Roland P.,

Drost, Jarno,

Grolleman, Judith E.,

Behjati, Sam,

Cuppen, Edwin,

Nik-Zainal, Serena,

Mizutani, Tomohiro,

Blokzijl, Francis

2017

Overview

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.

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Publisher

American Association for the Advancement of Science,The American Association for the Advancement of Science

Subject

Base excision repair

/ Breast cancer

/ Breast Neoplasms - genetics

/ Cancer

/ Colon

/ Colorectal cancer

/ Colorectal Neoplasms - genetics