Histo-genomic stratification reveals the frequent amplification/overexpression of CCNE1 and BRD4 genes in non-BRCAness high grade ovarian carcinoma
Histo-genomic stratification reveals the frequent amplification/overexpression of CCNE1 and BRD4 genes in non-BRCAness high grade ovarian carcinoma
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DOI：
10.1002/ijc.29568
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发表时间：
2015-10-15
影响因子：
6.4
通讯作者：
Sastre-Garau, Xavier
中科院分区：
文献类型：
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作者：
Goundiam, Oumou;Gestraud, Pierre;Sastre-Garau, Xavier
上皮性卵巢癌(EOC)的治疗是狭隘的，尽管这种疾病的异质性，其结果仍然很差。为了对卵巢癌患者进行有针对性的治疗，我们开发了一种整合了表达和基因组分析的方法，包括BRCAness状态。基因表达和基因组图谱用于鉴定105例EOC中重复扩增和过度表达的基因(>；5%)。应用BRCAness的LST(大规模状态转移)基因组签名来定义EOC的分子亚群。扩增/过表达基因主要集中在3q、8q、19p和19q。这些变化通常被发现是相互排斥的。在可确定基因组特征的85例患者中，52例(61.1%)为基因组BRCAness，33例(38.8%)为非BRCAness。在BRCAness和扩增/过表达数据之间观察到显著的互斥性。3q和8q改变多见于BRCAness EoC，19号染色体改变多见于非BRCAness病例。CCNE1(19q12)和BRD4(19p13.1)扩增/过表达在非BRCAness病例中有19/33例(57.5%)。在用于验证的TCGA EOC数据集中也发现了这种不平衡。在非BRCAness EoC中，潜在的靶基因经常被扩增/过度表达。我们报告已经在几种肿瘤模型中被确定为靶点的BRD4，是高级别非BRCacess卵巢癌的一个新的潜在靶点。
The treatment of epithelial ovarian cancer (EOC) is narrowly focused despite the heterogeneity of this disease in which outcomes remain poor. To stratify EOC patients for targeted therapy, we developed an approach integrating expression and genomic analyses including the BRCAness status. Gene expression and genomic profiling were used to identify genes recurrently (>5%) amplified and overexpressed in 105 EOC. The LST (Large-scale State Transition) genomic signature of BRCAness was applied to define molecular subgroups of EOC. Amplified/overexpressed genes clustered mainly in 3q, 8q, 19p and 19q. These changes were generally found mutually exclusive. In the 85 patients for which the genomic signature could be determined, genomic BRCAness was found in 52 cases (61.1%) and non-BRCAness in 33 (38.8%). A striking mutual exclusivity was observed between BRCAness and amplification/overexpression data. Whereas 3q and 8q alterations were preferentially observed in BRCAness EOC, most alterations on chromosome 19 were in non-BRCAness cases. CCNE1 (19q12) and BRD4 (19p13.1) amplification/overexpression was found in 19/33 (57.5%) of non-BRCAness cases. Such disequilibrium was also found in the TCGA EOC data set used for validation. Potential target genes are frequently amplified/overexpressed in non-BRCAness EOC. We report that BRD4, already identified as a target in several tumor models, is a new potential target in high grade non-BRCAness ovarian carcinoma.