Epigenetic state-control and immune visibility as prognostic modules in breast cancer.

Abstract

e12602 Background: Epigenetic reprogramming is proposed as an enabling dimension of cancer, but it remains unclear how expression programs of epigenetic regulators map onto downstream hallmark capabilities and clinical outcomes. We tested whether an expression-based “epigenetic state-control” module has a definable cancer hallmark footprint and subtype-specific prognostic relevance in breast cancer. Methods: We assembled a literature-derived 81-gene epigenetic state-control signature encompassing canonical chromatin regulatory systems (Polycomb, H3K9 repression, DNA methylation, SWI/SNF and NuRD remodeling, histone acetylation/deacetylation, arginine methylation, and 3D genome organization). The association with cancer hallmarks was evaluated using enrichment analysis on cancerhallmarks.com, with a multiple-testing correction (FDR). In parallel, we defined an 18-gene immune-visibility module that captures MHC-I antigen processing and presentation and IFN signaling. Prognostic performance for relapse-free survival (RFS) was assessed in KMplotter across PAM50 subtypes using the best cutoff, with multiple-testing adjustment (FDR < 10%). Results: The epigenetic regulator module showed broad hallmark associations, with strong enrichment for replicative immortality and genome instability, and additional enrichment for resisting cell death, metabolic reprogramming, and invasion-metastasis. In contrast, the epigenetic signature was not enriched for “evasion of immune destruction”. However, it was robustly captured by the immune-visibility module, supporting that immune evasion is best assessed using dedicated antigen presentation programs rather than inferred indirectly from chromatin regulators. In KMplotter, a higher epigenetic module score was associated with improved RFS in luminal A (HR 0.52, p = 0.00029) and luminal B (HR 0.61, p = 5×10⁻4), but not in basal-like or HER2-positive disease. Conversely, a higher immune-visibility score stratified RFS in basal-like (HR 0.32, p = 8.2×10⁻14), luminal B (HR 0.51, p = 3.5×10⁻5), and HER2-enriched tumors (HR 0.53, p = 1.4×10⁻4), but not luminal A. Conclusions: Epigenetic regulators exhibit a distributed hallmark footprint, dominated by immortality and genome instability. The divergent, subtype-specific prognostic patterns argue that epigenetic state-control and immune visibility are distinct axes, prioritizing tumors with high epigenetic state-control but low immune visibility as candidates for epi-drug combinations.