Yu Congyan, Shen Yong, Li Xuen
Department of General Surgery, Longshan Hospital of Cixi City, Ningbo, Zhejiang, P.R. China.
Department of Surgical Oncology, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P.R. China.
Medicine (Baltimore). 2025 Apr 4;104(14):e42076. doi: 10.1097/MD.0000000000042076.
Hydrogen sulfide (H2S) is a vital gasotransmitter involved in breast cancer (BC) pathogenesis. This study aims to employ hydrogen sulfide-related genes (HSRGs) for molecular classification of BC and, accordingly, to establish a robust prognostic risk signature. Transcriptomic, clinical, and mutational data of BC patients were collected from the cancer genome atlas and gene expression omnibus databases. Prognostic relevance was evaluated using Cox regression analysis, while consensus clustering analysis was employed for molecular subtyping. Gene expression profiles, prognosis, immune infiltration patterns, drug sensitivity, and response to immunotherapy were compared between subtypes. Multiple-gene prognostic features were developed and assessed along with a nomogram. The gene expression was validated in clinical samples using quantitative polymerase chain reaction. Among 282 HSRGs, 46 exhibited significant correlations with BC prognosis. Consensus clustering identified 2 distinct molecular subtypes (C1 and C2). C1 displayed significantly improved prognosis compared to C2, accompanied by increased infiltration of B cells, T cells, monocytes, and mast cells but decreased macrophage infiltration. Moreover, C1 demonstrated higher drug sensitivity and immunotherapeutic response relative to C2. Enrichment analysis revealed suppressed immune-related processes and pathways in C2 while cell cycle regulation and chromosomal processes were significantly activated. Additionally, a risk feature comprising 6 differentially expressed genes between subtypes was constructed; this feature performed well in prognostic prediction. Integration of this feature with other clinical parameters (radiotherapy/chemotherapy status, clinical stage, N stage) into a nomogram further enhanced prognostic accuracy. Clinical samples further validated the high expression of ATP13A5, LRTM2, MAFA, and SPDYC and the low expression of CYP4F12 and TNN in BC. Our findings highlight the clinical relevance of HSRGs in BC, providing a basis for precise molecular classification and prognosis evaluation. The developed risk feature and nomogram offer practical tools for guiding personalized treatment strategies in clinical practice.
硫化氢(H₂S)是一种参与乳腺癌(BC)发病机制的重要气体信号分子。本研究旨在利用硫化氢相关基因(HSRGs)对BC进行分子分类,并据此建立一个可靠的预后风险特征。从癌症基因组图谱和基因表达综合数据库中收集了BC患者的转录组、临床和突变数据。使用Cox回归分析评估预后相关性,同时采用一致性聚类分析进行分子亚型分类。比较了各亚型之间的基因表达谱、预后、免疫浸润模式、药物敏感性和免疫治疗反应。开发并评估了多基因预后特征以及列线图。使用定量聚合酶链反应在临床样本中验证基因表达。在282个HSRGs中,46个与BC预后显著相关。一致性聚类识别出2种不同的分子亚型(C1和C2)。与C2相比,C1的预后显著改善,同时B细胞、T细胞、单核细胞和肥大细胞的浸润增加,但巨噬细胞浸润减少。此外,C1相对于C2表现出更高的药物敏感性和免疫治疗反应。富集分析显示C2中免疫相关过程和通路受到抑制,而细胞周期调控和染色体过程被显著激活。此外,构建了一个包含各亚型之间6个差异表达基因的风险特征;该特征在预后预测中表现良好。将该特征与其他临床参数(放疗/化疗状态、临床分期、N分期)整合到列线图中进一步提高了预后准确性。临床样本进一步验证了BC中ATP13A5、LRTM2、MAFA和SPDYC的高表达以及CYP4F12和TNN的低表达。我们的研究结果突出了HSRGs在BC中的临床相关性,为精确的分子分类和预后评估提供了依据。所开发的风险特征和列线图为临床实践中指导个性化治疗策略提供了实用工具。