A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance
A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance
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DOI：
10.1016/j.annonc.2020.10.470
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发表时间：
2021-01-01
影响因子：
50.5
通讯作者：
Forment, J., V
中科院分区：
文献类型：
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作者：
Tobalina, L.;Armenia, J.;Forment, J., V
背景：BRCA1 或 BRCA2 (BRCA) 基因的种系突变易患遗传性乳腺癌和卵巢癌，其中大多数为 BRCA2，在胰腺癌和前列腺恶性肿瘤中也很常见。这些患者的肿瘤往往会丢失野生型 BRCA 基因的两个拷贝，这使得它们对铂类药物和聚（ADP-核糖）聚合酶抑制剂（PARPi）极其敏感，而这些药物是这些疾病环境中的首选治疗方法。具有恢复 BRCA 蛋白表达能力的逆转二次突变已在文献中记录为对这些治疗产生耐药性的真实机制。 患者和方法：我们分析了 327 名携带 BRCA1 或 BRCA2 突变的肿瘤患者（234 名卵巢癌患者、27 名乳腺癌患者、13 名胰腺癌患者、11 名前列腺癌患者和 42 名不明来源癌症患者）的 BRCA 基因（来自肿瘤或循环肿瘤 DNA）的已发表测序数据。铂类或 PARPi 治疗。结果：我们描述了该队列中 86 名患者的 269 例回复突变病例 (26.0%)。对回复事件的详细分析强调，BRCA1 和 BRCA2 中外显子 11 编码的大多数氨基酸序列对于产生铂或 PARPi 抗性来说是可有可无的，而其他区域更难以抵抗大量氨基酸损失。他们还强调了诱变末端连接DNA修复途径在产生回复中的关键作用，特别是在影响BRCA2的回复中，正如导致回复事件的缺失周围DNA序列微同源性的显着积累所表明的那样。结论：我们的分析表明，DNA末端连接修复途径的药理抑制可以通过防止BRCA基因中回复突变的获得来提高药物治疗的耐久性。他们还强调了当逆转导致 BRCA 蛋白亚等态表达时潜在的新治疗机会，特别是针对 DNA 复制应激反应的药物。
Background: Germline mutations in the BRCA1 or BRCA2 (BRCA) genes predispose to hereditary breast and ovarian cancer and, mostly in the case of BRCA2, are also prevalent in cases of pancreatic and prostate malignancies. Tumours from these patients tend to lose both copies of the wild-type BRCA gene, which makes them exquisitely sensitive to platinum drugs and poly(ADP-ribose) polymerase inhibitors (PARPi), treatments of choice in these disease settings. Reversion secondary mutations with the capacity of restoring BRCA protein expression have been documented in the literature as bona fide mechanisms of resistance to these treatments.Patients and methods: We analysed published sequencing data of BRCA genes (from tumour or circulating tumour DNA) in 327 patients with tumours harbouring mutations in BRCA1 or BRCA2 (234 patients with ovarian cancer, 27 with breast cancer, 13 with pancreatic cancer, 11 with prostate cancer and 42 with a cancer of unknown origin) that progressed on platinum or PARPi treatment.Results: We describe 269 cases of reversion mutations in 86 patients in this cohort (26.0%). Detailed analyses of the reversion events highlight that most amino acid sequences encoded by exon 11 in BRCA1 and BRCA2 are dispensable to generate resistance to platinum or PARPi, whereas other regions are more refractory to sizeable amino acid losses. They also underline the key role of mutagenic end-joining DNA repair pathways in generating reversions, especially in those affecting BRCA2, as indicated by the significant accumulation of DNA sequence microhomologies surrounding deletions leading to reversion events.Conclusions: Our analyses suggest that pharmacological inhibition of DNA end-joining repair pathways could improve durability of drug treatments by preventing the acquisition of reversion mutations in BRCA genes. They also highlight potential new therapeutic opportunities when reversions result in expression of hypomorphic versions of BRCA proteins, especially with agents targeting the response to DNA replication stress.