Comprehensive epigenomic and transcriptomic analysis identifies FABP7 and CLIC6 as methylation-driven prognostic...

Breast cancer (BRCA) is the most prevalent malignancy among women and exhibits significant molecular and clinical heterogeneity. To improve risk stratification and identify novel molecular subtypes, we employed integrative analysis on DNA CpG methylation and transcriptomic data to construct a methylation-driven prognostic model for BRCA. Using LASSO, we identified a 10-gene prognostic signature that effectively stratified patients into two groups designated as high-risk and low-risk groups. Kaplan-Mayer survival analysis revealed worse overall survival of the high-risk patients in the TCGA cohort (p < 0.0001). The risk model was independently validated in two external GEO datasets GSE86166 (p = 0.00011) and GSE42568 (p = 0.00013) demonstrating its resilience and clinical relevance. In addition, the risk groups were not associated with any canonical molecular subtypes of breast cancer. Among the 10 genes, FABP7 and CLIC6 were differentially expressed between the risk groups. FABP7 had the highest negative LASSO coefficients followed by CLIC6. In further analysis, FABP7 (R² = 0.42, p = 3e-04) and CLIC6 (R² = 0.48, P < 0.001) both showed a strong inverse correlation between CpG methylation and expression, with more than two-fold higher expression in low-risk group and linked to improved survival in all three independent cohort. Functional enrichment analysis identified that genes overexpressed in the low-risk subtype were significantly enriched in immune-related pathways. Immunological analysis indicated a more immunogenic tumor microenvironment in the FABP7 and CLIC6 positive, low-risk group, with significantly higher infiltration of CD8⁺ T cells (p = 0.047) and resting NK cells (p = 0.0391), while FABP7 and CLIC6 negative, high-risk tumors had increased M2 macrophages (p = 9.19 × 10^-6) and Tregs (p = 0.0122). To summarize, this integrative model identified a novel methylation-based risk classifier/molecular subtype for BRCA, highlighting FABP7 and CLIC6 as a key prognostic biomarker with potential utility for risk stratification for strategic treatment. These findings require further validation through wet-lab experiments and prospective clinical studies to support clinical translation.