小柯机器人

美国加州大学圣迭戈分校Ludmil B. Alexandrov研究小组发现，癌症聚集突变图谱揭示APOBEC3对ecDNA的诱变作用。这一研究成果于2022年2月9日在线发表在国际学术期刊《自然》上。

研究人员对30种类型癌症的2,583个全基因组测序中聚集替换和聚集小插入和缺失（indel）进行了全面的描述。聚集突变在驱动基因中高度富集，并与不同的基因表达和总生存率的变化有关。几个不同的突变过程产生了聚集indel，包括在吸烟者和同源重组缺陷的癌症中富集的特征。双碱基替换是由至少12个突变过程引起的，而大多数多碱基替换是由吸烟或暴露于紫外线产生的。omikli事件，以前曾被归因于APOBEC3的活动，占了聚集替换的很大一部分；然而，只有16.2%的omikli与APOBEC3的模式相匹配。

kataegis是由多种突变过程产生的，76.1%的kataegis事件表现出与活化诱导脱氨酶（AID）和APOBEC3脱氨酶家族有关的突变模式。在31%的有ecDNA的样本中发现了APOBEC3 kataegis和染色体外DNA（ecDNA）的共同出现，称为kyklonas（希腊语的旋风）。在大多数突变的ecDNA上观察到多个不同的kataegis事件。含有已知癌症基因的ecDNA同时表现出正选择和kataegis超突变。这些结果揭示了人类癌症中聚集突变过程的多样性以及APOBEC3在反复突变和助长ecDNA进化中的作用。

据了解，聚集体细胞突变在癌症基因组中很常见，以前的分析揭示了几种类型的集群单碱基替换，其中包括双碱基和多碱基替换，被称为omikli的弥漫性超突变，以及被称为kataegis的长链协调的事件。

附：英文原文

Title: Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA

Author: Bergstrom, Erik N., Luebeck, Jens, Petljak, Mia, Khandekar, Azhar, Barnes, Mark, Zhang, Tongwu, Steele, Christopher D., Pillay, Nischalan, Landi, Maria Teresa, Bafna, Vineet, Mischel, Paul S., Harris, Reuben S., Alexandrov, Ludmil B.

Issue&Volume: 2022-02-09

Abstract: Clustered somatic mutations are common in cancer genomes and previous analyses reveal several types of clustered single-base substitutions, which include doublet- and multi-base substitutions1,2,3,4,5, diffuse hypermutation termed omikli6, and longer strand-coordinated events termed kataegis3,7,8,9. Here we provide a comprehensive characterization of clustered substitutions and clustered small insertions and deletions (indels) across 2,583 whole-genome-sequenced cancers from 30 types of cancer10. Clustered mutations were highly enriched in driver genes and associated with differential gene expression and changes in overall survival. Several distinct mutational processes gave rise to clustered indels, including signatures that were enriched in tobacco smokers and homologous-recombination-deficient cancers. Doublet-base substitutions were caused by at least 12 mutational processes, whereas most multi-base substitutions were generated by either tobacco smoking or exposure to ultraviolet light. Omikli events, which have previously been attributed to APOBEC3 activity6, accounted for a large proportion of clustered substitutions; however, only 16.2% of omikli matched APOBEC3 patterns. Kataegis was generated by multiple mutational processes, and 76.1% of all kataegic events exhibited mutational patterns that are associated with the activation-induced deaminase (AID) and APOBEC3 family of deaminases. Co-occurrence of APOBEC3 kataegis and extrachromosomal DNA (ecDNA), termed kyklonas (Greek for cyclone), was found in 31% of samples with ecDNA. Multiple distinct kyklonic events were observed on most mutated ecDNA. ecDNA containing known cancer genes exhibited both positive selection and kyklonic hypermutation. Our results reveal the diversity of clustered mutational processes in human cancer and the role of APOBEC3 in recurrently mutating and fuelling the evolution of ecDNA.

DOI: 10.1038/s41586-022-04398-6

Source: https://www.nature.com/articles/s41586-022-04398-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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