APOBEC3 mutational signatures are associated with extensive and diverse genomic instability across multiple tumour types.
APOBEC3 mutational signatures are associated with extensive and diverse genomic instability across multiple tumour types.
复制标题
DOI：
10.1186/s12915-022-01316-0
复制
发表时间：
2022-05-21
期刊：
影响因子：
5.4
通讯作者：
Wedge, David C.
中科院分区：
文献类型：
--
作者：
Jakobsdottir, G. Maria;Brewer, Daniel S.;Cooper, Colin;Green, Catherine;Wedge, David C.
胞苷脱氨酶的APOBEC 3（载脂蛋白B mRNA编辑酶催化多肽3）家族负责在癌症基因组中发现的两个突变特征（SBS 2和SBS 13）。APOBEC 3酶响应于病毒感染而被激活，并且与增加的突变负荷和TP 53突变相关。除此之外，已经表明APOBEC 3活性可能通过产生双链断裂而导致不属于经典APOBEC 3特征（SBS 2和SBS 13）的突变。在这里，我们使用来自泛癌症全基因组分析（PCAWG）数据集中39种不同肿瘤类型的2451个原发性肿瘤的全基因组测序数据来研究APOBEC 3与基因组不稳定性（GI）之间的关系。我们发现经典APOBEC 3特征突变的数量与不同肿瘤类型中突变负荷的增加相关。此外，APOBEC 3突变的数量是六种不同GI指标的重要预测因子。两种GI测量（归因于INDEL标签ID 6和ID 8的INDEL）强烈地表明双链断裂的发生和易错修复，当排除归因于kataegis的SNV时，APOBEC 3突变和GI之间的关系仍然存在。我们提供的证据支持癌症基因组进化的模型，其中APOBEC 3作为一个致病因素，通过产生双链断裂。这对携带APOBEC 3突变的癌症的治疗方法具有重要意义，并挑战了APOBECs仅在单链DNA位点机会性作用的观点。在线版本包含补充材料，请访问（10.1186/s12915-022-01316-0）。
The APOBEC3 (apolipoprotein B mRNA editing enzyme catalytic polypeptide 3) family of cytidine deaminases is responsible for two mutational signatures (SBS2 and SBS13) found in cancer genomes. APOBEC3 enzymes are activated in response to viral infection, and have been associated with increased mutation burden and TP53 mutation. In addition to this, it has been suggested that APOBEC3 activity may be responsible for mutations that do not fall into the classical APOBEC3 signatures (SBS2 and SBS13), through generation of double strand breaks.Previous work has mainly focused on the effects of APOBEC3 within individual tumour types using exome sequencing data. Here, we use whole genome sequencing data from 2451 primary tumours from 39 different tumour types in the Pan-Cancer Analysis of Whole Genomes (PCAWG) data set to investigate the relationship between APOBEC3 and genomic instability (GI). We found that the number of classical APOBEC3 signature mutations correlates with increased mutation burden across different tumour types. In addition, the number of APOBEC3 mutations is a significant predictor for six different measures of GI. Two GI measures (INDELs attributed to INDEL signatures ID6 and ID8) strongly suggest the occurrence and error prone repair of double strand breaks, and the relationship between APOBEC3 mutations and GI remains when SNVs attributed to kataegis are excluded.We provide evidence that supports a model of cancer genome evolution in which APOBEC3 acts as a causative factor in the development of diverse and widespread genomic instability through the generation of double strand breaks. This has important implications for treatment approaches for cancers that carry APOBEC3 mutations, and challenges the view that APOBECs only act opportunistically at sites of single stranded DNA. The online version contains supplementary material available at (10.1186/s12915-022-01316-0).
登录
查看更多内容
B细胞中的突变，Kataegis和易位：了解有助于混杂活性。
DOI：
10.1038/nri.2016.2
发表时间：
2016-03
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
Casellas R;Basu U;Yewdell WT;Chaudhuri J;Robbiani DF;Di Noia JM
通讯作者：
Di Noia JM
影响因子：
--
作者：
Glaser AP;Fantini D;Wang Y;Yu Y;Rimar KJ;Podojil JR;Miller SD;Meeks JJ
通讯作者：
Meeks JJ
影响因子：
4.6
作者：
Mullane SA;Werner L;Rosenberg J;Signoretti S;Callea M;Choueiri TK;Freeman GJ;Bellmunt J
通讯作者：
Bellmunt J
DOI：
10.1186/s13058-014-0498-3
发表时间：
2015-01-21
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Harris RS
通讯作者：
Harris RS
影响因子：
7
作者：
Gillison, Maura L.;Akagi, Keiko;Symer, David E.
通讯作者：
Symer, David E.