SUPERTAM_HGU133A Gene Set Enrichment Analysis (GSEA) in term of lymph node and distant metastasis

Background Lymph node status is generally considered as one of the best prognostic factors in breast cancer. However, association between nodal and distant metastasis is not straightforward. Here we analyze differences between molecular mechanisms responsible for nodal and distant metastasis, and the impact of molecular subtype on this association. Methods We use SUPERTAM_HGU133A cohort of 836 patients with full microarray data available. Logistic regression evaluates distant metastasis risk, and Gene Set Enrichment Analysis (GSEA) is used to identify molecular mechanisms targetable in the key clinical scenarios. Results GSEA shows different molecular background for lymph node and distant metastasis and unique patterns of deregulated molecular processes in tumors of four breast cancer subtypes. Risk of distant metastasis in node positive luminal A patients is strong in SUPERTAM_HGU133A (OR: 2.401, CI: 1.316-4.380) dataset. For luminal A tumors, nodal positivity is associated with enrichment of NF-κB and Src, while distant metastasis is associated with strong mechanisms of cell cycle regulation, thrombolysis, DNA-repair, and immune response. Based on GSEA results, we select panels of promising inhibitors applicable for the key clinical scenarios depending on lymph node status that are currently being tested in vitro, in vivo, or in clinical trials. Conclusions Potential molecular targets are different for nodal and distant metastasis in breast cancer and are highly variable among different molecular subtypes. Panels of inhibitors have potential to improve the outcome of luminal A breast cancer patients based on lymph node status. We hope that further clinical trials have potential to translate the current knowledge from the laboratory to an improved treatment of breast cancer patients.

背景 淋巴结状态通常被视为乳腺癌最佳预后因素之一。然而，淋巴结转移与远处转移之间的关联并非直观简单。本研究旨在分析介导淋巴结转移与远处转移的分子机制差异，以及分子亚型对该关联的影响。方法 本研究纳入包含836例患者的SUPERTAM_HGU133A队列，所有受试者均具备完整的微阵列数据。采用逻辑回归模型评估远处转移风险，并通过基因集富集分析（Gene Set Enrichment Analysis, GSEA）识别关键临床场景下的可靶向分子机制。结果 GSEA分析显示，淋巴结转移与远处转移具有不同的分子背景，且四种乳腺癌亚型的肿瘤中存在失调分子进程的独特模式。在SUPERTAM_HGU133A数据集中，淋巴结阳性的腔A型（luminal A）患者的远处转移风险显著升高（比值比OR=2.401，95%置信区间CI=1.316-4.380）。对于腔A型肿瘤，淋巴结阳性与NF-κB及Src通路的富集相关，而远处转移则与细胞周期调控、溶栓、DNA修复及免疫应答等核心分子机制密切关联。基于GSEA分析结果，我们筛选出可根据淋巴结状态应用于关键临床场景的潜在抑制剂组合，此类抑制剂目前正处于体外、体内实验或临床试验阶段。结论 乳腺癌中介导淋巴结转移与远处转移的潜在分子靶点存在差异，且在不同分子亚型间差异显著。根据淋巴结状态选择适配的抑制剂组合，有望改善腔A型乳腺癌患者的临床预后。我们期待后续开展的临床试验能够将当前的实验室研究成果转化为更优化的乳腺癌患者治疗方案。

搜集汇总

背景与挑战

背景概述

该数据集基于SUPERTAM_HGU133A队列（836名乳腺癌患者）的基因表达数据，通过基因集富集分析（GSEA）研究淋巴结转移和远处转移的分子机制差异。分析发现，淋巴结和远处转移的分子背景不同，且不同乳腺癌亚型（如luminal A）中失调的分子过程具有独特模式，例如淋巴结阳性与NF-κB和Src富集相关，而远处转移与细胞周期调控、血栓溶解等机制相关。研究结果为基于淋巴结状态的靶向治疗提供了潜在分子靶点。