APOBEC mediated mutagenesis drives genomic heterogeneity in endometriosis
APOBEC mediated mutagenesis drives genomic heterogeneity in endometriosis
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APOBEC 介导的突变驱动子宫内膜异位症的基因组异质性
DOI：
10.1038/s10038-021-01003-y
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发表时间：
2022
影响因子：
3.5
通讯作者：
Inoue Ituro
中科院分区：
文献类型：
--
作者：
Revathidevi Sundaramoorthy;Nakaoka Hirofumi;Suda Kazuaki;Fujito Naoko;Munirajan Arasambattu Kannan;Yoshihara Kosuke;Enomoto Takayuki;Inoue Ituro
子宫内膜异位症是一种良性妇科疾病，是卵巢癌某些组织学亚型的前兆。子宫内膜异位症组织和正常子宫内膜上皮细胞积累了肿瘤相关基因如磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α (PIK3CA)和克尔斯顿大鼠肉瘤（KRAS）原癌基因的体细胞突变。为了确定子宫内膜异位症上皮细胞和正常子宫内膜的基因组特征，并确定作用于它们的主要突变过程，我们研究了从14个子宫内膜异位症上皮细胞和11个正常子宫内膜组织的全外显子组测序中获得的体细胞突变谱，并将它们分类为突变特征。我们观察到，载脂蛋白B mRNA编辑酶催化亚单位（APOBEC）诱导的突变导致的单碱基替换2/13 （SBS）在子宫内膜异位症组织中显著，但在正常子宫内膜中不显著。此外，与子宫内膜异位症的癌症相关驱动突变相比，APOBEC特征突变的数量和等位基因频率分布更广，这表明APOBEC突变是子宫内膜异位症突变负担和异质性的重要来源。此外，携带apobec3a / 3b种系缺失的子宫内膜异位症患者，APOBEC特征突变富集的相对风险更高，apobec3a / 3b种系缺失是东亚人常见的多态性，涉及apobec3b编码区完全缺失。我们的研究结果说明了APOBEC诱导的突变在驱动子宫内膜异位症的基因组异质性中的重要性。
Endometriosis is a benign gynecologic condition, acting as a precursor of certain histological subtypes of ovarian cancers. The epithelial cells of endometriotic tissues and normal uterine endometrium accumulated somatic mutations in cancer-associated genes such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha(PIK3CA) and Kirsten rat sarcoma (KRAS)proto-oncogene. To determine the genomic characteristic of endometriotic epithelial cells and normal uterine endometrium and to identify the predominant mutational process acting on them, we studied the somatic mutation profiles obtained from whole exome sequencing of 14 endometriotic epithelium and 11 normal uterine endometrium tissues and classified them into mutational signatures. We observed that single base substitutions 2/13 (SBS), attributed to Apolipoprotein B mRNA Editing Enzyme Catalytic Subunit (APOBEC) induced mutagenesis, were significant in endometriotic tissues, but not in the normal uterine endometrium. Additionally, the larger number and wider allele frequency distribution of APOBEC signature mutations, compared to cancer-associated driver mutations in endometriotic epithelium suggested APOBEC mutagenesis as an important source of mutational burden and heterogeneity in endometriosis. Further, the relative risk of enriched APOBEC signature mutations was higher in endometriosis patients who were carriers ofAPOBEC3A/3Bgermline deletion, a common polymorphism in East Asians which involves the complete loss ofAPOBEC3Bcoding region. Our results illustrate the significance of APOBEC induced mutagenesis in driving the genomic heterogeneity of endometriosis.
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影响因子：
16.6
作者：
Caval, Vincent;Suspene, Rodolphe;Wain-Hobson, Simon
通讯作者：
Wain-Hobson, Simon
DOI：
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发表时间：
--
期刊：
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影响因子：
--
作者：
通讯作者：
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影响因子：
11.5
作者：
Yamaguchi, Ken;Mandai, Masaki;Fujii, Shingo
通讯作者：
Fujii, Shingo
影响因子：
3.5
作者：
Adachi, Sosuke;Tajima, Atsushi;Tanaka, Kenichi
通讯作者：
Tanaka, Kenichi
影响因子：
5.7
作者：
Suda, Kazuaki;Diaz, Luis Antonio Cruz;Enomoto, Takayuki
通讯作者：
Enomoto, Takayuki