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 CRISPR-mediated genome editing of organoids can reveal the origin of mutational signatures in human cancer. 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.

中文翻译：

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使用 CRISPR 修饰的人类干细胞类器官研究癌症突变特征的起源

类器官的特征事件人类癌症基因组具有神秘的突变特征，这些特征代表了 DNA 损伤和 DNA 修复过程中缺陷的累积效应。了解特定特征的来源可能会对癌症的诊断和预防产生重大影响。解决这个问题的一种方法是通过基因工程在实验系统中复制特征，然后将特征与在自然发生的癌症中发现的特征相匹配。德罗斯特等人。使用 CRISPR-Cas9 从人类结肠类器官中删除某些 DNA 修复酶。在一项概念验证研究中，他们表明，碱基切除修复的缺陷是先前在癌症基因组测序项目中发现的突变特征的原因。科学，本期第 3 页。234 CRISPR 介导的类器官基因组编辑可以揭示人类癌症中突变特征的起源。突变过程是癌症发生和进展的基础。癌症基因组中这些过程的特征可以解释癌症病因，并具有诊断和预后价值。我们开发了一种策略，可用于探索癌症相关突变特征的起源。我们使用 CRISPR-Cas9 技术删除人类结肠类器官中的关键 DNA 修复基因，然后进行延迟亚克隆和全基因组测序。我们发现错配修复基因 MLH1 缺陷的类器官中的突变积累是由复制错误驱动的，并准确地模拟了在错配修复缺陷的结直肠癌中观察到的突变谱。将该策略应用于癌症易感基因 NTHL1，其编码碱基切除修复蛋白，揭示了先前在乳腺癌队列中观察到的突变足迹（特征 30）。我们表明特征 30 可能来自种系 NTHL1 突变。