Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas
Frequent Homologous Recombination Deficiency in High-grade Endometrial Carcinomas
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DOI：
10.1158/1078-0432.ccr-18-1443
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发表时间：
2019-02-01
影响因子：
11.5
通讯作者：
Bosse, Tjalling
中科院分区：
文献类型：
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作者：
de Jonge, Marthe M.;Auguste, Aurelie;Bosse, Tjalling
目的：高风险子宫内膜癌子集中体细胞拷贝数改变（SCNA）水平升高表明控制基因组完整性的途径存在缺陷。我们试图评估子宫内膜癌中同源重组缺陷 (HRD) 的患病率及其与组织病理学和分子特征的关系。 实验设计：前瞻性地从 36 例子宫内膜癌中收集新鲜肿瘤组织，通过复制肿瘤细胞在电离辐射诱导的 DNA 双链断裂（RAD51 病灶）处积累 RAD51 蛋白的能力来检查功能性 HRD。基因组改变通过下一代测序和阵列比较基因组杂交/SNP阵列来确定。 BRCA 相关基因组疤痕（HRD 的替代标志物）的患病率在癌症基因组图谱 (TCGA) 子宫内膜癌队列中确定。结果：最终分析 (n = 25) 中包含的大多数子宫内膜癌为非子宫内膜样癌 (52%)、组织学 3 级 (60%) 和 Figo I 期 (72%)。在 24%（n = 6）的病例中观察到 HRD，且仅限于非子宫内膜样子宫内膜癌 (NEEC)，其中 46% 的 NEEC 存在 HRD，而子宫内膜样子宫内膜癌则没有 (EEC, P = 0.014)。除 1 例外，所有 HRD 病例均携带致病性 BRCA1 变异或 HR 基因高体细胞拷贝数 (SCN) 丢失。 TCGA 病例分析支持了这些结果，NEEC 中高达 48% (63/132) 存在 BRCA 相关基因组疤痕，而 EEC 中这一比例为 12% (37/312) (P < 0.001)。结论：HRD 发生在子宫内膜癌中，并且主要限于非子宫内膜样、TP53 突变子宫内膜癌。 HRD 评估可能有助于选择可受益于针对该缺陷的治疗（包括铂化合物和 PARP 抑制剂）的患者。
Purpose: The elevated levels of somatic copy-number alterations (SCNAs) in a subset of high-risk endometrial cancers are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in endometrial cancers and its association with histopathologic and molecular characteristics.Experimental Design: Fresh tumor tissue was prospectively collected from 36 endometrial cancers, and functional HRD was examined by the ability of replicating tumor cells to accumulate RAD51 protein at DNA double-strand breaks (RAD51 foci) induced by ionizing radiation. Genomic alterations were determined by next-generation sequencing and array comparative genomic hybridization/SNP array. The prevalence of BRCA-associated genomic scars, a surrogate marker for HRD, was determined in the The Cancer Genome Atlas (TCGA) endometrial cancer cohort.Results: Most endometrial cancers included in the final analysis (n = 25) were of non-endometrioid (52%), grade 3 (60%) histology, and FIGO stage I (72%). HRD was observed in 24%(n = 6) of cases and was restricted to non-endometrioid endometrial cancers (NEEC), with 46% of NEECs being HRD compared with none of the endometrioid endometrial cancers (EEC, P = 0.014). All but 1 of the HRD cases harbored either a pathogenic BRCA1 variant or high somatic copy-number (SCN) losses of HR genes. Analysis of TCGA cases supported these results, with BRCA-associated genomic scars present in up to 48% (63/132) of NEEC versus 12% (37/312) of EEC (P < 0.001).Conclusions: HRD occurs in endometrial cancers and is largely restricted to non-endometrioid, TP53-mutant endometrial cancers. Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors.