Whole-exome and targeted capture sequencing of fibroepithelial tumors; fibroadenomas and phyllodes tumors

Breast fibroepithelial tumors, which affect millions of women annually, comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas (FAs) to malignant phyllodes tumors (PTs)1. While MED12 mutations have been frequently found in FAs and PTs2-7, the landscapes of genetic alterations across the fibroepithelial tumor spectrum remain unclear. Here, by performing exome-sequencing of 22 PTs followed by targeted-sequencing of 100 breast fibroepithelial tumors, we observed three distinct somatic mutation patterns. First, MED12 and RARA mutations were frequently observed in both FAs and PTs, emphasizing their importance in fibroepithelial tumorigenesis. Second, PTs exhibited mutations in FLNA, SETD2 and KMT2D, suggesting a role in driving PT development. Third, borderline/malignant PTs harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the ligand-binding domain, functionally suppressed RARA-mediated transcriptional activation and enhanced RARA interactions with transcriptional co-repressors. This study provides insights into the molecular pathogenesis of breast fibroepithelial tumors, with potential clinical implications