Uncovering the Molecular Secrets of Inflammatory Breast Cancer Biology: An Integrated Analysis of Three Distinct Affymetrix Gene Expression Datasets
Uncovering the Molecular Secrets of Inflammatory Breast Cancer Biology: An Integrated Analysis of Three Distinct Affymetrix Gene Expression Datasets
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DOI：
10.1158/1078-0432.ccr-12-2549
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发表时间：
2013-09-01
影响因子：
11.5
通讯作者：
Bertucci, Francois
中科院分区：
文献类型：
--
作者：
Van Laere, Steven J.;Ueno, Naoto T.;Bertucci, Francois
背景：炎性乳腺癌（IBC）是一种特征性不强的乳腺癌。由于样本量有限等原因，目前IBC表达谱的研究结果还不确定。在这里，我们提出了整合的三个Affyphase表达数据集收集通过世界IBC联盟，使我们能够询问IBC的分子概况使用最大的系列IBC samples ever reported.Experimental Design：Affyphase配置文件（HGU 133系列）从137例IBC和252例非IBC（nIBC）进行了分析，使用无监督和监督技术。使用PAM 50算法根据分子亚型对样品进行分类。回归模型用于描述IBC特异性和分子亚型无关的基因表达、途径和转录因子激活的变化。（P < 0.001），除管腔A亚型外，所有亚型在IBC中的检出率与nIBC相似（19%对42%; P < 0.001）和HER 2富集亚型（22%对9%; P < 0.001）。监督分析识别并验证了IBC特异性、分子亚型独立的79个基因特征，其在一系列871个nIBC中具有独立的预后价值。功能分析显示衰减TGF-β信号在IBC.Conclusion：我们表明，IBC是转录异质性和nIBC中描述的所有分子亚型在IBC中检测到，虽然具有不同的频率。具有侵袭性乳腺肿瘤生物学的分子特征的IBC的分子谱显示TGF-β信号传导的减弱，这可能以意想不到的方式解释了IBC肿瘤细胞的转移潜力。（C）2013年AACR。
Background: Inflammatory breast cancer (IBC) is a poorly characterized form of breast cancer. So far, the results of expression profiling in IBC are inconclusive due to various reasons including limited sample size. Here, we present the integration of three Affymetrix expression datasets collected through the World IBC Consortium allowing us to interrogate the molecular profile of IBC using the largest series of IBC samples ever reported.Experimental Design: Affymetrix profiles (HGU133-series) from 137 patients with IBC and 252 patients with non-IBC (nIBC) were analyzed using unsupervised and supervised techniques. Samples were classified according to the molecular subtypes using the PAM50-algorithm. Regression models were used to delineate IBC-specific and molecular subtype-independent changes in gene expression, pathway, and transcription factor activation.Results: Four robust IBC-sample clusters were identified, associated with the different molecular subtypes (P < 0.001), all of which were identified in IBC with a similar prevalence as in nIBC, except for the luminal A subtype (19% vs. 42%; P < 0.001) and the HER2-enriched subtype (22% vs. 9%; P < 0.001). Supervised analysis identified and validated an IBC-specific, molecular subtype-independent 79-gene signature, which held independent prognostic value in a series of 871 nIBCs. Functional analysis revealed attenuated TGF-beta signaling in IBC.Conclusion: We show that IBC is transcriptionally heterogeneous and that all molecular subtypes described in nIBC are detectable in IBC, albeit with a different frequency. The molecular profile of IBC, bearing molecular traits of aggressive breast tumor biology, shows attenuation of TGF-beta signaling, potentially explaining the metastatic potential of IBC tumor cells in an unexpected manner. (C)2013 AACR.