MAGEA12 expression, prognostic significance, and Antigenicity in invasive Ductal carcinoma breast cancer

Abstract

Background: The heterogeneity of breast cancer (BC) significantly influences treatment, creating a need for new therapies effective across molecular subtypes. Invasive Ductal Carcinoma (IDC), the most common and aggressive form of BC, often exhibits resistance to conventional therapies. Melanoma Associated Antigen 12 (MAGEA12), frequently associated with aggressive cancers such as IDC, is a promising immunotherapy target. Identifying its putative epitopes may facilitate peptide vaccine and novel immunotherapy design against IDC. Methods: We used 4 transcriptomics datasets (the three MAGEA12 mRNA splice variants, 576 IDC cases from TCGA, 40 BC cell lines SRA samples, and 10,000 CDR3β TCR sequences) to identify MAGE12 peptides that can be exploited for immunotherapy in IDC. Differential expression analysis was done with DESeq2, survival associations with Cox models, peptide-MHC binding with NetMHCpan 4.1a, and TCR-pMHC interactions with pMTnet. Results: MAGEA12 was significantly overexpressed across all BC subtypes (adj p-value< 0.05) compared to normal tissue, with highest levels in non-luminal (Basal, HER2+) and second to MAGEA1 in luminal (A & B) subtypes. Its expression correlated with poor survival in Luminal A patients (ρ = 0.0189). From 15,759 predicted peptides, 690 bound strongly to 64 genotyped MHC I alleles, forming 2,710 stable, high-affinity TCR-pMHC complexes with CDR3β TCR sequences. Conclusion: These findings reveal novel immunogenic MAGEA12-derived peptides capable of forming strong TCR-pMHC interactions, supporting MAGEA12 as a promising target for antigen-based immunotherapy in IDC. We provide a prioritized repertoire of peptides for experimental validation and development of MAGEA12-directed cancer vaccines and immune interventions.