生物
清脆的
MLH1
癌症
DNA错配修复
遗传学
癌变
种系突变
癌症研究
突变
DNA修复
计算生物学
结直肠癌
基因
作者
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
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2017-10-13
卷期号:358 (6360): 234-238
被引量:343
标识
DOI:10.1126/science.aao3130
摘要
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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