BRCA1-Mutated Estrogen Receptor-Positive Breast Cancer Shows BRCAness, Suggesting Sensitivity to Drugs Targeting Homologous Recombination Deficiency
BRCA1-Mutated Estrogen Receptor-Positive Breast Cancer Shows BRCAness, Suggesting Sensitivity to Drugs Targeting Homologous Recombination Deficiency
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DOI：
10.1158/1078-0432.ccr-16-0198
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发表时间：
2017-03-01
影响因子：
11.5
通讯作者：
Nederlof, Petra M.
中科院分区：
文献类型：
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作者：
Lips, Esther H.;Debipersad, Rashmie D.;Nederlof, Petra M.
目的：由于BRCA 1突变携带者中的雌激素受体阳性（ER+）乳腺癌发生在年龄较大时，肿瘤特征不如ER阴性（ER-）BRCA 1突变乳腺癌，因此有人认为这些肿瘤是“散发性”的，而不是BRCA 1驱动的。随着针对具有无功能BRCA 1或BRCA 2基因的肿瘤的靶向治疗的引入，BRCA基因是否在肿瘤中受损的问题高度相关。因此，我们进行了BRCA 1突变的ER+ tumors.Experimental设计基因组分析，BRCA 1启动子甲基化评估，和杂合性丢失分析16 BRCA 1突变的ER+肿瘤。结果：BRCA 1突变的ER+肿瘤的基因组谱不同于BRCA 1突变的ER-乳腺肿瘤，但与BRCA 2突变的ER+肿瘤高度相似。在83%的BRCA 1突变的ER+肿瘤中，观察到野生型BRCA 1等位基因的丢失。此外，BRCA 1突变的ER+癌的临床病理变量也更类似于BRCA 2突变的ER+和散发性ER+乳腺癌比BRCA 1突变的ER- cancers.Conclusions：BRCA 1突变的ER+肿瘤显示BRCA-ness拷贝数配置文件和洛，这是可能的，功能性BRCA 1蛋白的损失在BRCA 1突变的ER+肿瘤的肿瘤发生中发挥作用。因此，我们假设这些肿瘤对靶向BRCA 1基因缺陷的药物敏感，为晚期BRCA缺陷、ER+乳腺癌提供了新的靶向治疗方式。（C）2016年AACR。
Purpose: As estrogen receptor-positive (ER+) breast cancer in BRCA1 mutation carriers arises at an older age with less aggressive tumor characteristics than ER-negative (ER-) BRCA1-mutated breast cancer, it has been suggested that these tumors are "sporadic" and not BRCA1 driven. With the introduction of targeted treatments specific for tumors with a nonfunctioning BRCA1 or BRCA2 gene, the question whether the BRCA genes are impaired in the tumor is highly relevant. Therefore, we performed genomic profiling of BRCA1-mutated ER+ tumors.Experimental Design: Genomic profiling, BRCA1 promoter methylation assessment, and loss of heterozygosity analysis were done on 16 BRCA1-mutated ER+ tumors. Results were compared with 57 BRCA1-mutated ER- tumors, 36 BRCA2-mutated ER+ -associated tumors, and 182 sporadic ER+ tumors.Results: The genomic profile of BRCA1-mutated ER+ tumors was different from BRCA1-mutated ER- breast tumors, but highly similar to BRCA2-mutated ER+ tumors. In 83% of the BRCA1-mutated ER+ tumors, loss of the wild-type BRCA1 allele was observed. In addition, clinicopathologic variables in BRCA1-mutated ER+ cancer were also more similar to BRCA2-mutated ER+ and sporadic ER+ breast cancer than to BRCA1-mutated ER- cancers.Conclusions: As BRCA1-mutated ER+ tumors show a BRCA-ness copy number profile and LOH, it is likely that the loss of a functional BRCA1 protein plays a role in tumorigenesis in BRCA1-mutated ER+ tumors. Therefore, we hypothesize that these tumors are sensitive to drugs targeting the BRCA1 gene defect, providing new targeted treatment modalities for advanced BRCA-deficient, ER+ breast cancer. (C)2016 AACR.