Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes
Biological processes associated with breast cancer clinical outcome depend on the molecular subtypes
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DOI：
10.1158/1078-0432.ccr-07-4756
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发表时间：
2008-08-15
影响因子：
11.5
通讯作者：
Sotiriou, Christos
中科院分区：
文献类型：
--
作者：
Desmedt, Christine;Haibe-Kains, Benjamin;Sotiriou, Christos
目的：最近，已经鉴定了几种预后基因表达特征;然而，它们的性能从未根据先前描述的基于雌激素受体（ER）和人表皮生长因子受体2（HER 2）的分子亚型进行评估，并且它们的生物学意义仍然不清楚。在此，我们旨在进行一项综合性荟萃分析，整合临床病理学和基因表达数据，重点关注主要的分子亚型。我们开发了与乳腺癌关键生物学过程相关的基因表达模块，如肿瘤侵袭、免疫反应、血管生成、凋亡、增殖以及ER和HER 2信号传导，然后分析这些模块与临床变量和公开可用的微阵列研究的几个预后标志结果：多因素分析显示，在ER+/HER 2-亚组中，只有增殖模块和组织学分级与临床结局显著相关。在ER-/HER 2-亚组中，仅免疫应答模块与预后相关，而在HER 2+肿瘤中，肿瘤侵袭和免疫应答模块显示与生存显著相关。增殖被认为是几个预后标志的最重要组成部分，其表现仅限于ER+/HER 2-亚组。虽然增殖是预测ER+/HER 2-亚型临床结果的最强参数，也是大多数预后基因特征的共同点，免疫应答和肿瘤侵袭似乎分别是与ER-/HER 2-和HER 2+亚组的预后相关的主要分子过程。这些发现可能有助于定义新的临床基因组学模型，并确定新的治疗策略，在特定的分子亚组。
Purpose: Recently, several prognostic gene expression signatures have been identified; however, their performance has never been evaluated according to the previously described molecular subtypes based on the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2), and their biological meaning has remained unclear. Here we aimed to perform a comprehensive meta-analysis integrating both clinicopathologic and gene expression data, focusing on the main molecular subtypes.Experimental Design: We developed gene expression modules related to key biological processes in breast cancer such as tumor invasion, immune response, angiogenesis, apoptosis, proliferation, and ER and HER2 signaling, and then analyzed these modules together with clinical variables and several prognostic signatures on publicly available microarray studies (>2,100 patients).Results: Multivariate analysis showed that in the ER+/HER2- subgroup, only the proliferation module and the histologic grade were significantly associated with clinical outcome. In the ER-/HER2- subgroup, only the immune response module was associated with prognosis, whereas in the HER2+ tumors, the tumor invasion and immune response modules displayed significant association with survival. Proliferation was identified as the most important component of several prognostic signatures, and their performance was limited to the ER+/HER2- subgroup.Conclusions: Although proliferation is the strongest parameter predicting clinical outcome in the ER+/HER2- subtype and the common denominator of most prognostic gene signatures, immune response and tumor invasion seem to be the main molecular processes associated with prognosis in the ER-/HER2- and HER2+ subgroups, respectively. These findings may help to define new clinicogenomic models and to identify new therapeutic strategies in the specific molecular subgroups.