Templated Insertions Are Associated Specifically with BRCA2 Deficiency and Overall Survival in Advanced Ovarian Cancer.
Templated Insertions Are Associated Specifically with BRCA2 Deficiency and Overall Survival in Advanced Ovarian Cancer.
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DOI：
10.1158/1541-7786.mcr-21-1012
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发表时间：
2022-07-06
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同源重组 (HR) 缺陷的癌细胞对 DNA 交联化疗、PARP 抑制剂和聚合酶 θ 抑制剂有反应，聚合酶 θ 是备用途径替代末端连接的关键介质。此类癌症包括核心 HR 基因中存在致病性双等位基因改变的癌症，以及对相同药物表现出敏感性并具有 HR 缺陷 (HRD) 基因组特征的另一组病例。这些 HRD 特征包括单碱基替换模式、大的重排、特征串联重复和小缺失。在这里，我们利用目前已知的通过关键因子聚合酶 theta 的备用途径替代末端连接 (Alt-EJ) 来设计和测试聚合酶 theta 介导 (TMEJ) 修复的新特征。我们生成了两个新颖的签名；一个由具有微同源性的小缺失组成的签名，另一个由小的模板化插入组成。我们发现，与 TMEJ 修复一致的模板插入 (TINS) 对于 BRCA2 致病性双等位基因突变的肿瘤具有高度特异性，并且晚期卵巢癌中高 TINS 基因组特征含量与铂类药物治疗后的总体生存率相关。此外，与当前最先进的特征相比，TINS 与其他 HRD 指标的结合显着改善了铂敏感性与生存的关联。
Cancer cells defective in homologous recombination (HR) are responsive to DNA crosslinking chemotherapies, PARP inhibitors, and inhibitors of polymerase theta, a key mediator of the backup pathway alternative end-joining. Such cancers include those with pathogenic bi-allelic alterations in core HR genes and another cohort of cases that exhibit sensitivity to the same agents and harbor genomic hallmarks of HR deficiency (HRD). These HRD signatures include a single base substitution pattern, large rearrangements, characteristic tandem duplications, and small deletions. Here, we utilized what is now known about the backup pathway alternative end-joining (Alt-EJ) through the key factor polymerase theta to design and test novel signatures of polymerase theta mediated (TMEJ) repair. We generated two novel signatures; a signature composed of small deletions with microhomology and another consisting of small, templated insertions. We find that templated insertions (TINS) consistent with TMEJ repair are highly specific to tumors with pathogenic bi-allelic mutations in BRCA2 and that high TINS genomic signature content in advanced ovarian cancers associate with overall survival following treatment with platinum agents. Additionally, the combination of TINS with other HRD metrics significantly improves the association of platinum sensitivity with survival compared to current state-of-the-art signatures.