Nonequivalent Gene Expression and Copy Number Alterations in High-Grade Serous Ovarian Cancers with BRCA1 and BRCA2 Mutations
Nonequivalent Gene Expression and Copy Number Alterations in High-Grade Serous Ovarian Cancers with BRCA1 and BRCA2 Mutations
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DOI：
10.1158/1078-0432.ccr-13-0066
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发表时间：
2013-07-01
影响因子：
11.5
通讯作者：
Bowtell, David D.
中科院分区：
文献类型：
--
作者：
George, Joshy;Alsop, Kathryn;Bowtell, David D.
目的：高级别浆液性癌（HGSC）占上皮性卵巢癌死亡的大部分。基因组和功能数据表明，大约一半未选择的 HGSC 具有 BRCA 途径破坏和同源重组修复 (HRR) 缺陷。通路破坏被认为会赋予 BRCAness 表型。我们探索了 HGSC 中与特定 BRCA1/BRCA2 体细胞或种系突变以及 BRCA1 DNA 启动子甲基化相关的分子变化。实验设计：我们描述了两大组 HGSC 的基因表达和拷贝数分析，其中测量了 HRR 的种系和体细胞失活。结果：BRCA1 破坏与 HGSC 的 C2（免疫反应性）分子亚型相关，其特点是肿瘤内 T 细胞强烈渗透。我们衍生并验证了 BRCA1 突变或甲基化状态的预测因子，但无法区分 BRCA2 和野生型肿瘤。 DNA拷贝数分析显示，BRCA1突变病例与8q24（频率：BRCA1肿瘤50%，BRCA2肿瘤32%，野生型肿瘤9%）和基底样乳腺癌中X染色体特定失调区域（BLBC；BRCA1 62%，BRCA2 34%，野生型35%）的扩增显着相关。与 BRCA1/BRCA2 突变相关的肿瘤与 19p13（BRCA1 0%、BRCA2 3% 和野生型 20%）和 19q12（BRCA1 6%、BRCA2 3% 和野生型 29%）的扩增呈负相关。 结论：与 BRCA1 突变相关的肿瘤与 BRCA2 突变相关的肿瘤之间的分子差异与新出现的临床和病理数据一致，并支持对HGSC 和 BLBC 之间的关系。 (C)2013 AACR。
Purpose: High-grade serous carcinoma (HGSC) accounts for the majority of epithelial ovarian cancer deaths. Genomic and functional data suggest that approximately half of unselected HGSC have disruption of the BRCA pathway and defects in homologous recombination repair (HRR). Pathway disruption is regarded as imparting a BRCAness phenotype. We explored the molecular changes in HGSC arising in association with specific BRCA1/BRCA2 somatic or germline mutations and in those with BRCA1 DNA promoter methylation.Experimental Design: We describe gene expression and copy number analysis of two large cohorts of HGSC in which both germline and somatic inactivation of HRR has been measured.Results: BRCA1 disruptions were associated with the C2 (immunoreactive) molecular subtype of HGSC, characterized by intense intratumoral T-cell infiltration. We derived and validated a predictor of BRCA1 mutation or methylation status, but could not distinguish BRCA2 from wild-type tumors. DNA copy number analysis showed that cases with BRCA1 mutation were significantly associated with amplification both at 8q24 (frequencies: BRCA1 tumors 50%, BRCA2 tumors 32%, and wild-type tumors 9%) and regions of the X-chromosome specifically dysregulated in basal-like breast cancer (BLBC; BRCA1 62%, BRCA2 34%, and wild-type 35%). Tumors associated with BRCA1/BRCA2 mutations shared a negative association with amplification at 19p13 (BRCA1 0%, BRCA2 3%, and wild-type 20%) and 19q12 (BRCA1 6%, BRCA2 3%, and wild-type 29%).Conclusion: The molecular differences between tumors associated with BRCA1 compared with BRCA2 mutations are in accord with emerging clinical and pathologic data and support a growing appreciation of the relationship between HGSC and BLBC. (C)2013 AACR.