MED12is frequently mutated in breast phyllodes tumours: a study of 112 cases

Abstract

AimTo determine the frequency of MED12 mutations in a series of 112 breast phyllodes tumours, and to correlate the findings with clinicopathological parameters and survival outcomes. Methods Phyllodes tumours from the Department of Pathology, Singapore General Hospital, were classified into benign, borderline and malignant categories. Genomic DNA from formalin-fixed paraffin-embedded phyllodes tumours was extracted, purified and subjected to ultra-deep-targeted amplicon sequencing across exon 2 of the MED12 gene. Sequencing was performed on the Illumina MiSeq next-generation sequencing platform and bioinformatics analysis applied. Appropriate statistical analyses were carried out. Results There were 66 benign, 32 borderline and 14 malignant tumours, with 43 (65.1%), 21 (65.6%) and 6 (42.8%) disclosing MED12 mutations (missense, splice site, indel), respectively. For 97 cases with available follow-up, there were 10 (10.3%) recurrences. Patients with phyllodes tumours that harboured MED12 mutations experienced improved disease-free survivals, with higher recurrence likelihood in those without MED12 mutations (HR 9.99, 95% CIs 1.55 to 64.42, p=0.015). Conclusions Similar to fibroadenomas, phyllodes tumours show a high frequency of MED12 mutations, affirming the close biological relationship between these fibroepithelial neoplasms.

MED12 protein expression in breast fibroepithelial lesions: correlation with mutation status and oestrogen receptor expression

“…These cases were partly derived from our previous study cohorts 1 2. Samples were obtained from the archives of the Department of Pathology, Singapore General Hospital with ethics approval from the Centralized Institutional Review Board (CIRB 2005/002/F).…”

“…Fibroadenomas and phyllodes tumours are the two major entities of fibroepithelial lesions. Our recent studies reported frequent somatic MED12 mutations in both fibroadenomas (59%) and phyllodes tumours (62.5%) 1 2 . MED12 encodes for the mediator complex subunit 12 (MED12) protein, which assembles with other subunits to form a large protein complex known as the mediator complex.…”

Distant metastases in phyllodes tumours of the breast: an overview

“…Recent molecular developments in PTs have revealed insights into the pathogenesis of PTs, in particular the identification of recurrent mediator complex subunit 12 (MED12) somatic mutations, found in fibroadenomas and all grades of PTs [42][43][44][45]. Mutations in FLNA (28.0%), SETD2 (21.0%) and KMT2D (9.0%) were also discovered, which are believed to contribute to tumour progression in PTs [46].…”

Genomic landscapes of breast fibroepithelial tumors

“…Fibroadenoma-like areas are frequent in phyllodes tumors, and some studies have proposed a clonal progression from fibroadenomas to phyllodes tumors [10][11][12][13][14] . At the molecular level, frequent MED12 exon 2 mutations have been observed in fibroepithelial tumors [2][3][4][5][6][7]15 , and increased rates of copy number alteration (CNA) have been associated with phyllodes tumors of higher grade 16,17 . Recent profiling of a small number of phyllodes tumors identified recurrent mutations in TP53 and singleton mutations in RB1 and NF1 exclusively in higher-grade phyllodes tumors 15 .…”