Subtype-specific ZMYND10 expression as a potential novel prognostic and treatment marker for ER-positive/HER2-negative breast cancer

Abstract Breast cancer (BC) is a heterogeneous malignant tumor that currently lacks reliable biomarkers. Identifying such biomarkers would enable better risk stratification and present potential treatment options for estrogen receptor positive/human epidermal growth factor receptor 2 negative (ER+/HER2-) disease. This study uses transcriptomic, genomic, and clinical data from the TCGA, METABRIC, GSE96058, GSE25066, and GSE20194 cohorts to investigate the prognostic and therapeutic relevance of ZMYND10 through immunohistochemical validation. We evaluated the correlations between ZMYND10 expression and clinical pathological features, survival rate, tumor mutation burden (TMB), immune and stromal infiltration, neoadjuvant chemotherapy (NAC) responses, and immune checkpoint inhibitor sensitivity. We found that ZMYND10 expression is enriched in both luminal and ER+/HER2- tumors, and is associated with lower pathological grading, T staging, clinical staging, and improved survival, especially in the ER+/HER2- subtype. Tumors with low ZMYND10 expression exhibit increased inflammation, immune-related PI3K/AKT/mTOR signaling, glycolytic and cell cycle pathway enrichment, and anti-tumor and immunosuppressive immune cell infiltration. Low ZMYND10 expression is associated with higher TMB and distinct mutation patterns, including more TP53 alterations. Conversely, PIK3CA and MAP3K1 alterations are more common in tumors with high ZMYND10 expression. Although an association with a complete pathological response to NAC was observed, it was not consistent across the cohort. The prognostic nomogram combining ZMYND10 and the relevant clinical variables showed good differentiation. Further computational analysis indicates that tumors with low ZMYND10 expression are more sensitive to PD-1 blockade. These findings identify ZMYND10 as a potential subtype-specific prognostic biomarker and therapeutic stratification marker in ER+/HER2- breast cancer that warrants prospective and functional validation.