Frontiers in Genetics (Mar 2025)
Identification of mitochondrial permeability transition-related lncRNAs as quantitative biomarkers for the prognosis and therapy of breast cancer
Abstract
Breast cancer (BC) continues to pose a global health threat and presents challenges for treatment due to its high heterogeneity. Recent advancements in the understanding of mitochondrial permeability transition (MPT) and the regulatory roles of long non-coding RNAs (lncRNAs) offer potential insights for the stratification and personalized treatment of BC. Although the association between MPT and lncRNAs has not been widely studied, a few research studies have indicated a regulatory impact of lncRNAs on MPT, further deepening the understanding of the tumor. To identify reliable biomarkers associated with MPT for managing BC, bulk RNA-seq data of MPT-related lncRNAs acquired from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project were utilized to assess BC patients. A scoring system, termed the MPT-related score (MPTRscore), was developed using LASSO-Cox regression on data from 1,029 BC patients from TCGA-BRCA. Meanwhile, the superior prognostic accuracy of the MPTRscore was demonstrated by comparing it with biomarkers, including PAM50 subtyping for standardization. Subsequently, a clinical prediction model was created by incorporating the MPTRscore and clinical variables. This analysis revealed two distinct MPTRscore groups characterized by different biomolecular processes, tumor microenvironment (TME) patterns, and clinical outcomes. The MPTRscore was further investigated through unsupervised consensus clustering of TCGA-BRCA based on MPTRscore-related prognostic genes. Additionally, the MPTRscore was identified as an independent prognostic factor for BC and showed guiding utility in immunotherapy and chemotherapy response. Specifically, patients with a low MPTRscore exhibited better prognosis and treatment responses compared to those with a high MPTRscore. Significantly, the relevance of clustering results and MPTRscore was found to be mediated by lncRNA transcript RP11-573D15.8-018. In conclusion, MPTRscore-related clusters were identified in BC, and an integrative score was developed as a biomarker for predicting BC prognosis and therapeutic response. Additionally, molecular interactions underlying the relationship between MPTRscore-related clusters and MPTRscore were uncovered, proving insights for BC stratification. These findings may aid in prognosis determination and therapeutic decision-making for BC patients.
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