Microhomology-mediated break-induced replication (MMBIR) is a DNA repair pathway initiated by polymerase template switching at microhomology, which can produce templated insertions that initiate chromosomal rearrangements leading to neurological and metabolic diseases, and promote complex genomic rearrangements (CGRs) found in cancer. Yet, how often templated insertions accumulate from processes like MMBIR in genomes is poorly understood due to difficulty in directly identifying these events by whole genome sequencing (WGS). Here, by using our newly developed MMBSearch software, we directly detect such templated insertions (MMB-TIs) in human genomes and report substantial differences in frequency and complexity of MMB-TI events between normal and cancer cells. Through analysis of 71 cancer genomes from The Cancer Genome Atlas (TCGA), we observed that MMB-TIs readily accumulate de novo across several cancer types, with particularly high accumulation in some breast and lung cancers. By contrast, MMB-TIs appear only as germline variants in normal human fibroblast cells, and do not accumulate as de novo somatic mutations. Finally, we performed WGS on a lung adenocarcinoma patient case and confirmed MMB-TI-initiated chromosome fusions that disrupted potential tumor suppressors and induced chromothripsis-like CGRs. Based on our findings we propose that MMB-TIs represent a trigger for widespread genomic instability and tumor evolution.

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癌细胞对与 MMBIR 相关的模板化插入的积累高度敏感

微同源介导的断裂诱导复制 (MMBIR) 是一种由聚合酶模板转换在微同源启动的 DNA 修复途径，它可以产生模板插入，启动导致神经和代谢疾病的染色体重排，并促进癌症中发现的复杂基因组重排 (CGRs) . 然而，由于难以通过全基因组测序 (WGS) 直接识别这些事件，因此对基因组中 MMBIR 等过程中模板插入的累积频率知之甚少。在这里，通过使用我们新开发的 MMBSearch 软件，我们直接检测人类基因组中的此类模板插入 (MMB-TI)，并报告正常细胞和癌细胞之间 MMB-TI 事件的频率和复杂性存在显着差异。通过分析来自癌症基因组图谱 (TCGA) 的 71 个癌症基因组，我们观察到 MMB-TI 很容易在几种癌症类型中从头积累，在一些乳腺癌和肺癌中积累特别高。相比之下，MMB-TI 仅作为正常人成纤维细胞中的种系变体出现，并且不会作为从头体细胞突变积累。最后，我们对一个肺腺癌患者病例进行了 WGS，并证实了 MMB-TI 引发的染色体融合破坏了潜在的肿瘤抑制因子并诱导了染色体碎裂样 CGR。根据我们的发现，我们提出 MMB-TI 代表了广泛的基因组不稳定性和肿瘤进化的触发因素。并且不会以从头体细胞突变的形式积累。最后，我们对一个肺腺癌患者病例进行了 WGS，并证实了 MMB-TI 引发的染色体融合破坏了潜在的肿瘤抑制因子并诱导了染色体碎裂样 CGR。根据我们的发现，我们提出 MMB-TI 代表了广泛的基因组不稳定性和肿瘤进化的触发因素。并且不会以从头体细胞突变的形式积累。最后，我们对一个肺腺癌患者病例进行了 WGS，并证实了 MMB-TI 引发的染色体融合破坏了潜在的肿瘤抑制因子并诱导了染色体碎裂样 CGR。根据我们的发现，我们提出 MMB-TI 代表了广泛的基因组不稳定性和肿瘤进化的触发因素。