Integrative multi-omics reveals common and distinct pathogenic mechanisms and preoperative diagnostic signatures in breast fibroepithelial lesions

Breast fibroepithelial lesions (FELs) comprising fibroadenomas (FAs) and phyllodes tumors (PTs) with varying degrees of malignancy, necessitate tailored surgical approaches. However, preoperative diagnosis of FELs remains challenging and their pathogenesis is not fully elucidated. By integrating methylation and expression data, we revealed substantial molecular deregulation common to FAs and PTs, impacting pathways central to genetic information processing and metabolism. Furthermore, we identified 86 genes exhibiting concurrent differential expression and methylation changes between FAs and PTs, some of which have been implicated in the malignant progression of disease. Subsequently, we constructed two gene-pair signatures: one comprising 158 pairs for distinguishing FAs from PTs, and another with 146 pairs for differentiating benign from malignant PTs. Both signatures achieved AUC exceeding 0.85 in independent surgical and core biopsy datasets. Finally, we identified 99 pathogenic genes exhibiting continuous up-regulation or down-regulation from FAs to malignant PTs. Significant associations were observed between these genes and key cancer-related biological pathways.