Background: Fumarate hydratase (FH) deficiency is a rare metabolic alteration in breast cancer that may drive tumor progression through angiogenic remodeling. However, its role in shaping the tumor microenvironment remains poorly defined, limiting our understanding of metabolism-driven angiogenesis and its therapeutic significance.Methods: We analyzed genomic and transcriptomic profiles from thousands of breast cancer samples, including the TCGA cohort, to identifyFHmutations and copy number alterations. Differential expression, pathway enrichment, and weighted gene co-expression network analysis (WGCNA) were performed to characterize metabolic and signaling changes. Clinical relevance was examined in a triple-negative breast cancer patient with anFHmutation treated with bevacizumab.Results:FHalterations were enriched in larger, primary tumors and in older patients.FH-deficient tumors displayed metabolic reprogramming, with reduced oxidative phosphorylation and TCA cycle activity, accompanied by upregulation of angiogenesis, VEGF signaling, and epithelial–mesenchymal transition pathways. WGCNA identified 11 hub genes (including CDH5, CLDN5, VWF, and PECAM1) linked to a pro-angiogenic microenvironment. A clinical case illustrated a durable and exceptional response to bevacizumab-based therapy in anFH-mutant patient.Conclusions:FHdeficiency promotes an angiogenic tumor microenvironment and may serve as a predictive biomarker for VEGF-targeted therapies. These findings underscore the therapeutic potential of exploiting metabolic vulnerabilities to inform precision oncology.
背景：延胡索酸水合酶（FH）缺陷是乳腺癌中一种罕见的代谢改变，可能通过血管生成重塑驱动肿瘤进展。然而，其在塑造肿瘤微环境中的作用仍不明确，限制了我们对代谢驱动血管生成及其治疗意义的理解。 方法：我们分析了包括TCGA队列在内的数千例乳腺癌样本的基因组和转录组数据，以识别FH突变和拷贝数变异。通过差异表达分析、通路富集分析和加权基因共表达网络分析（WGCNA）来表征代谢和信号通路变化。在一例接受贝伐珠单抗治疗的FH突变三阴性乳腺癌患者中检验了其临床相关性。 结果：FH改变在体积较大的原发肿瘤和老年患者中更为常见。FH缺陷肿瘤表现出代谢重编程，包括氧化磷酸化和三羧酸循环活性降低，同时伴随血管生成、VEGF信号通路和上皮-间质转化通路上调。WGCNA分析确定了11个与促血管生成微环境相关的枢纽基因（包括CDH5、CLDN5、VWF和PECAM1）。临床病例显示，一例FH突变患者对基于贝伐珠单抗的治疗产生了持久且显著的应答。 结论：FH缺陷促进血管生成性肿瘤微环境，可能作为VEGF靶向治疗的预测性生物标志物。这些发现强调了利用代谢脆弱性指导精准肿瘤学治疗的潜力。
肿瘤(癌症)患者之家