POSTN/TGFBI-associated stromal signature predicts poor prognosis in serous epithelial ovarian cancer
POSTN/TGFBI-associated stromal signature predicts poor prognosis in serous epithelial ovarian cancer
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DOI：
10.1016/j.ygyno.2013.12.021
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发表时间：
2014-02-01
影响因子：
4.7
通讯作者：
Slamon, Dennis
中科院分区：
文献类型：
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作者：
Karlan, Beth Y.;Dering, Judy;Slamon, Dennis
Objective.通过对高级别浆液性上皮性卵巢癌（EOC）发病机制的生物学特征进行遗传学分析，确定其分子生物学指标和治疗靶点。卵巢组织样本（n = 172; 122浆液性卵巢上皮性卵巢癌，30其他卵巢上皮性卵巢癌，20正常/良性）收集前瞻性的连续进行妇科手术的患者进行了分析，使用RNA表达微阵列。基于与卵巢癌潜在相关的基因表达对样品进行分类。使用Rosetta相似性搜索工具（ROAST）和方差分析（ANOVA）定义基因集。采用基因芯片比较基因组杂交技术鉴定基因拷贝数变异。通过无监督聚类无法确定EOC的不同亚组，然而，基于与骨膜蛋白（POSTIN）和雌激素受体-α（ESR 1）相关的基因的分析产生了不同的亚组。当基于ANOVA比较ESR 1/WT 1和POR 4/TGFBI样本的基因对95例高级别浆液性EOC进行分组时，与52例表达ESR 1/WT 1相关基因的肿瘤患者相比，43例表达POR 4/TGFBI相关基因的肿瘤患者的总生存期（OS）显著较短（中位数分别为30个月和49个月; P = 0.022）。在每个亚组中确定了几个具有治疗潜力的靶点。BRCA种系突变在ESR 1/WT 1亚组中更常见。肿瘤相关基因和TP 53状态（突变型或野生型）与生存率无关。研究结果使用独立的卵巢癌细胞进行了验证。两个不同的分子亚组的高级别浆液性EOCs的基础上POR 4/TGFBI和ESR 1/WT 1的表达被确定为具有显着不同的OS。这些亚组之间的特定差异表达基因提供了潜在的预后和治疗靶点。(C)2013 Elsevier Inc. All rights reserved.
Objective. To identify molecular prognosticators and therapeutic targets for high-grade serous epithelial ovarian cancers (EOCs) using genetic analyses driven by biologic features of EOC pathogenesis.Methods. Ovarian tissue samples (n = 172; 122 serous EOCs, 30 other EOCs, 20 normal/benign) collected prospectively from sequential patients undergoing gynecologic surgery were analyzed using RNA expression microarrays. Samples were classified based on expression of genes with potential relevance in ovarian cancer. Gene sets were defined using Rosetta Similarity Search Tool (ROAST) and analysis of variance (ANOVA). Gene copy number variations were identified by array comparative genomic hybridization.Results. No distinct subgroups of EOC could be identified by unsupervised clustering, however, analyses based on genes correlated with periostin (POSTN) and estrogen receptor-alpha (ESR1) yielded distinct subgroups. When 95 high-grade serous EOCs were grouped by genes based on ANOVA comparing ESR1/WT1 and POSTN/TGFBI samples, overall survival (OS) was significantly shorter for 43 patients with tumors expressing genes associated with POSTN/TGFBI compared to 52 patients with tumors expressing genes associated with ESR1/WT1 (median 30 versus 49 months, respectively; P = 0.022). Several targets with therapeutic potential were identified within each subgroup. BRCA germline mutations were more frequent in the ESR1/WT1 subgroup. Proliferation-associated genes and TP53 status (mutated or wild-type) did not correlate with survival. Findings were validated using independent ovarian cancer datasets.Conclusions. Two distinct molecular subgroups of high-grade serous EOCs based on POSTN/TGFBI and ESR1/WT1 expressions were identified with significantly different OS. Specific differentially expressed genes between these subgroups provide potential prognostic and therapeutic targets. (C) 2013 Elsevier Inc. All rights reserved.