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Phyllodes tumors (PTs) and fibroadenomas (FAs) are fibroepithelial lesions (FELs) of the breast. Although mutations affecting exon 2 of  MED12  are highly recurrent in FAs and PTs,  TERT  promoter hotspot mutations are frequently found in PTs but are vanishingly rare in FAs. Malignant transformation of benign PTs is well-documented, but the progression from FA to PT remains a matter of contention. Here we report on the somatic genetic alterations in multiple ipsilateral synchronous FELs (three FAs, one benign PT, and one malignant PT) occurring in the same patient. DNA samples extracted from each tumor and matched normal tissue were subjected to targeted massively parallel sequencing using the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay. This analysis revealed  MED12  mutations in all lesions. One FA and the benign PT harbored a  MED12  Gly44Val  mutation, whereas another FA and the malignant PT displayed a  MED12  Gly44Asp  mutation. The remaining FA had an independent distinct  MED12  Gly44Cys  mutation. A formal clonality analysis suggested a clonal relationship between the FELs with identical  MED12  mutations ( P <0.05). A clonal  TERT  promoter hotspot mutation was identified exclusively in the malignant PT. The identification of distinct  MED12  mutations in multifocal ipsilateral and synchronous FELs supports the notion that co-existing mammary fibroepithelial tumors can arise independently. Conversely, the co-existence of identical  MED12  mutations indicates clonal relatedness among FAs and PTs, corroborating the hypothesis that FAs may constitute the substrate from which PTs develop. Our findings also support the notion that acquisition of  TERT  promoter mutations may drive the progression of FELs.

Massively parallel sequencing analysis of synchronous fibroepithelial lesions supports the concept of progression from fibroadenoma to phyllodes tumor