Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition
Enhanced GAB2 Expression Is Associated with Improved Survival in High-Grade Serous Ovarian Cancer and Sensitivity to PI3K Inhibition
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DOI：
10.1158/1535-7163.mct-15-0039
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发表时间：
2015-06-01
影响因子：
5.7
通讯作者：
Gorringe, Kylie L.
中科院分区：
文献类型：
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作者：
Davis, Sally J.;Sheppard, Karen E.;Gorringe, Kylie L.
确定确定卵巢癌亚型的基因组改变可能有助于对接受靶向治疗的患者进行分层。我们利用卵巢肿瘤组织分析队列中499名HGSC患者的基因表达数据，分析了11个拷贝数扩增基因：ATP13A4、BMP8B、CACNA1C、CCNE1、DYRK1B、GAB2、PAK4、RAD21、TPX2、ZFP36和URI与高级别浆液性卵巢癌(HGSC)的相关性。澳大利亚卵巢癌研究和癌症基因组图谱数据集也被用来评估基因表达、患者生存和肿瘤分类之间的相关性。在多因素分析中，GAB2的高表达与总生存率和无进展生存率的改善有关(P=0.004.0 3和0.0 2)，而BMP8B和ATP13A4的高表达与无进展生存率的改善有关(P=0.0 3和P=0.0 2)。AOCs C4亚组GAB2表达增强，拷贝数增加。GAB2的高表达与体外对双重PI3K/mTOR抑制剂PF-04691502的敏感性增强相关，可以作为一个基因组标记来识别对抑制PI3K信号转导的治疗有反应的患者。(C)2015年AACR。
Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of amplified and over-expressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number amplified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling. (C) 2015 AACR.