Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA.
Mapping clustered mutations in cancer reveals APOBEC3 mutagenesis of ecDNA.
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DOI：
10.1038/s41586-022-04398-6
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发表时间：
2022-03
期刊：
影响因子：
64.8
通讯作者：
Alexandrov LB
中科院分区：
文献类型：
--
作者：
Bergstrom EN;Luebeck J;Petljak M;Khandekar A;Barnes M;Zhang T;Steele CD;Pillay N;Landi MT;Bafna V;Mischel PS;Harris RS;Alexandrov LB
聚集性体细胞突变在癌症基因组中很常见，先前的分析揭示了几种类型的聚集性单碱基替换，其中包括双碱基和多碱基替换，称为omikli的弥漫性超突变，以及称为kataegis的较长链协调事件。在这里，我们提供了来自30种癌症的2583种全基因组测序癌症的聚集性替换和聚集性小插入和缺失(INDELs)的综合特征。聚集性突变在驱动基因中高度丰富，并与差异基因表达和总生存期的变化有关。几个不同的突变过程导致了聚集的Indels，包括在吸烟者和同源重组缺陷癌症中丰富的特征。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在紫外线下产生的。Omikli事件以前被归因于APOBEC3活性，在聚集性替换中占很大比例；然而，只有16.2%的omikli与APOBEC3模式匹配。Kataegis是由多个突变过程产生的，所有Kataegic事件中有76.1%表现出与激活诱导脱氨酶(AID)和APOBEC3脱氨酶家族相关的突变模式。在31%的ecDNA样本中发现APOBEC3 kataegis和染色体外DNA(EcDNA)共存，称为kykLonas(希腊语中气旋的意思)。在大多数突变的ecDNA上观察到多个不同的kyclon事件。含有已知癌基因的ecDNA既表现为正选择，也表现为染色体超突变。我们的结果揭示了人类癌症中聚集性突变过程的多样性，以及APOBEC3在反复突变和推动ecDNA进化中的作用。对30种癌症类型的簇状替换和Indels的分析提供了对APOBEC3通过其在染色体外DNA上的活性而在引起簇状突变事件中的作用的洞察。
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 substitutions, diffuse hypermutation termed omikli, and longer strand-coordinated events termed kataegis. 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 cancer. 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 activity, 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. An analysis of clustered substitutions and indels across 30 cancer types provides insight into the role of APOBEC3 in giving rise to clustered mutation events through its activity on extrachromosomal DNA.
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