线粒体通透性转换驱动的坏死相关模型的鉴定与多维度验证，以评估乳腺癌的预后和免疫治疗价值

Identification and multi-dimensional validation of mitochondrial permeability transition-driven necrosis-related model to assess the prognosis and immunotherapy value in breast cancer.

作者信息

Liu Jinsong, Wei Tong, Quan Liuliu, Dou Min, Yue Jian, Yuan Peng

机构信息

Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

出版信息

Eur J Med Res. 2025 Feb 18;30(1):113. doi: 10.1186/s40001-025-02370-4.

DOI:10.1186/s40001-025-02370-4

PMID:39966932

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11834492/

Abstract

BACKGROUND

Breast cancer is a highly prevalent tumor worldwide. Mitochondrial permeability transition (MPT)-driven necrosis is a novel type of cell death induced by mitochondrial membrane disruption. The roles of MPT-driven necrosis in breast cancer remain unclear.

METHODS

Gene expression and clinicopathologic features were extracted from The Cancer Genome Atlas and Gene Expression Omnibus. We performed a genome landscape analysis of MPT-driven necrosis (MPTdn)-related genes, and a consensus clustering analysis was conducted to construct MPTdn clusters. Next, a risk model was established based on the differentially expressed genes related to MPTdn. We grouped and used external data sets to verify the stability of the model. Subsequently, immune correlation analysis, clinical correlation assessment and drug sensitivity analysis were conducted. Finally, candidate genes were validated in the protein and mRNA levels.

RESULTS

A total of 39 MPTdn-related genes were identified in our analysis. Most MPTdn-related genes had different expression levels and somatic mutations in breast cancer, and a close interaction was noted among them. A risk model composed of BCL2A1, SCUBE2, NPY1R and CLIC6 was constructed. The low-risk group had better overall survival and higher immune infiltration levels. All three external data sets achieved excellent predictive efficacy. Finally, the immunohistochemistry results indicated that BCL2A1, SCUBE2, NPY1R and CLIC6 were expressed at significantly lower levels in breast cancer tissues, and the transcriptome sequencing results revealed that BCL2A1 and SCUBE2 mRNA expression levels were greater in the nonrecurrence group.

CONCLUSIONS

We developed a risk model with excellent predictive efficacy based on MPTdn and revealed that BCL2A1, SCUBE2, NPY1R and CLIC6 could be used as the biomarkers, laying a solid foundation for investigations of therapeutic targets of breast cancer.

摘要

背景

乳腺癌是全球范围内高度流行的肿瘤。线粒体通透性转换（MPT）驱动的坏死是一种由线粒体膜破坏诱导的新型细胞死亡。MPT驱动的坏死在乳腺癌中的作用仍不清楚。

方法

从癌症基因组图谱和基因表达综合数据库中提取基因表达和临床病理特征。我们对MPT驱动的坏死（MPTdn）相关基因进行了基因组景观分析，并进行了一致性聚类分析以构建MPTdn簇。接下来，基于与MPTdn相关的差异表达基因建立了风险模型。我们对外部数据集进行分组并用于验证模型的稳定性。随后，进行了免疫相关性分析、临床相关性评估和药物敏感性分析。最后，在蛋白质和mRNA水平上对候选基因进行了验证。

结果

我们的分析共鉴定出39个MPTdn相关基因。大多数MPTdn相关基因在乳腺癌中具有不同的表达水平和体细胞突变，并且它们之间存在密切的相互作用。构建了由BCL2A1、SCUBE2、NPY1R和CLIC6组成的风险模型。低风险组具有更好的总生存期和更高的免疫浸润水平。所有三个外部数据集均具有出色的预测效能。最后，免疫组织化学结果表明，BCL2A1、SCUBE2、NPY1R和CLIC6在乳腺癌组织中的表达水平显著降低，转录组测序结果显示非复发组中BCL2A1和SCUBE2的mRNA表达水平更高。