Frequent MED12 mutations in phyllodes tumours of the breast

Abstract

Background:Phyllodes tumours are rare fibroepithelial tumours of the breast, that include benign, borderline, and malignant lesions. Although the molecular basis of phyllodes tumours largely remains unknown, a recent exome study identified MED12 mutations as a sole recurrent genetic alteration in fibroadenoma, a common benign fibroepithelial tumour that shares some histological features with the phyllodes tumour.Methods:Forty-six phyllodes tumours and 58 fibroadenomas of the breast were analysed for MED12 mutations by using Sanger sequencing.Results:MED12 mutations were identified in 37 out of the 46 phyllodes tumours (80%). The prevalence of MED12 mutations was similar among benign (15/18, 83%), borderline (12/15, 80%), and malignant tumours (10/13, 77%). MED12 mutations were also identified in 36 of the 58 fibroadenomas (62%). The mutations were frequent among intracanalicular-type (24/32, 75%) and complex-type lesions (4/6, 67%), but were significantly less common among the pericanalicular-type lesions (8/20, 40%). A microdissection-based analysis showed that MED12 mutations were confined to the stromal components in both phyllodes tumours and fibroadenomas.Conclusions:MED12 mutations were frequent among the phyllodes tumours of the breast, regardless of the tumour grade. Phyllodes tumours and fibroadenomas share, at least in part, a common genetic background.

Mutational analysis of MED12 in fibroadenomas and phyllodes tumors of the breast by means of targeted next-generation sequencing

“…More recently, Cani [14,15]. Similar results have been reported by other investigators [16][17][18].…”

“…Most of these studies, however, used Sanger sequencing, and only a small number of tumors were analyzed with a more sensitive technique such as NGS [9,14], so that the mutation frequency may have been underestimated. Moreover, MED12 mutation frequency has rarely been studied by taking into account the histological type of FAs [15,17], while synchronous or metachronous multiple FAs in the breast, though not infrequent, have also rarely been studied [17]. For the present study, we therefore used mutational analysis of MED12 in FAs and PTs by means of NGS with special reference to the relationship of MED12 mutation with histological subtypes of FAs.…”

Phyllodes Tumor of the Breast: Histopathologic Features, Differential Diagnosis, and Molecular/Genetic Updates

“…In addition, MED12 is frequently mutated in all PTs. 6,7,9,51,52 These findings suggest both entities may share genetic etiology, and MDM2 mutation is an early event of fibroadenoma and PT pathogenesis. In a recent study by Tan et al, 10 exome sequencing of 22 PTs and targeted sequencing of 100 fibroepithelial tumors exhibited the genetic landscapes of fibroepithelial tumors, with frequent MED12 (73%) and RARA (32%) mutations in both fibroadenoma and all grades of PT.…”

“…The most recent genome sequencing studies have identified frequent MDM12 somatic mutations in fibroadenoma and PT, suggesting these 2 entities may share a common origin. [6][7][8][9][10] This review will address some of the diagnostic problems that are encountered in routine practice and provide molecular/genetic updates on PTs of the breast.…”

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].…”