Dataset Information

MED12 somatic mutations in fibroadenomas and phyllodes tumours of the breast.

ABSTRACT: Somatic mutations in exon 2 of the mediator complex subunit 12 (MED12) gene have been identified in 60% of breast fibroadenomas (FAs). The aim of this study was to define whether phyllodes tumours (PTs) would harbour MED12 somatic mutations in a way akin to FAs.A collection of 73 fibroepithelial tumours (including 26 FAs, 25 benign PTs, nine borderline PTs and 13 malignant PTs) from 64 patients was retrieved from the authors' institution. Sections from formalin-fixed paraffin-embedded (FFPE) blocks were microdissected to ensure an enrichment in neoplastic stromal elements of >70%. DNA samples extracted from tumour and matched normal tissues were subjected to Sanger sequencing of exon 2 of the MED12 gene. MED12 exon 2 somatic mutations, including 28 somatic single nucleotide variants and 19 insertions and deletions, were found in 65%, 88%, 78% and 8% of FAs, benign PTs, borderline PTs and malignant PTs, respectively. Malignant PTs harboured MED12 exon 2 somatic mutations significantly less frequently than FAs, benign and borderline PTs.Although MED12 exon 2 somatic mutations probably constitute the driver genetic event of most FAs, benign and borderline PTs, our results suggest that the majority of malignant PTs may be driven by other genetic/epigenetic alterations.

SUBMITTER: Piscuoglio S

PROVIDER: S-EPMC4996373 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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MED12 somatic mutations in fibroadenomas and phyllodes tumours of the breast.

Piscuoglio Salvatore S Murray Melissa M Fusco Nicola N Marchiò Caterina C Loo Florence L FL Martelotto Luciano G LG Schultheis Anne M AM Akram Muzaffar M Weigelt Britta B Brogi Edi E Reis-Filho Jorge S JS

Histopathology 20150524 5

<h4>Aims</h4>Somatic mutations in exon 2 of the mediator complex subunit 12 (MED12) gene have been identified in 60% of breast fibroadenomas (FAs). The aim of this study was to define whether phyllodes tumours (PTs) would harbour MED12 somatic mutations in a way akin to FAs.<h4>Methods and results</h4>A collection of 73 fibroepithelial tumours (including 26 FAs, 25 benign PTs, nine borderline PTs and 13 malignant PTs) from 64 patients was retrieved from the authors' institution. Sections from fo ...[more]

PMID: 25855048

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Project description:Fibroepithelial tumors (FTs) of the breast are a heterogeneous group of lesions ranging from fibroadenomas (FAD) to phyllodes tumors (PT) (benign, borderline, malignant). Further understanding of their molecular features and classification might be of clinical value. In this study, we analysed the expression of 105 breast cancer-related genes, including the 50 genes of the PAM50 intrinsic subtype predictor and 12 genes of the Claudin-low subtype predictor, in a panel of 75 FTs (34 FADs, 5 juvenile FADs, 20 benign PTs, 5 borderline PTs and 11 malignant PTs) with clinical follow-up. In addition, we compared the expression profiles of FTs with those of 14 normal breast tissues and 49 primary invasive ductal carcinomas (IDCs). Our results revealed that the levels of expression of all breast cancer-related genes can discriminate the various groups of FTs, together with normal breast tissues and IDCs (False Discovery Rate < 5%). Among FTs, the levels expression of proliferation-related genes (e.g. CCNB1 and MKI67) and mesenchymal/epithelial-related (e.g. CLDN3 and EPCAM) genes were found to be most discriminative. As expected, FADs showed the highest and lowest expression of epithelial- and proliferation-related genes, respectively, whereas malignant PTs showed the opposite expression pattern. Interestingly, the overall profile of benign PTs was found more similar to FADs and normal breast tissues than the rest of tumours, including juvenile FADs. Within the dataset of IDCs and normal breast tissues, the vast majority of FADs, juvenile FADs, benign PTs and borderline PTs were identified as Normal-like by intrinsic breast cancer subtyping, whereas 7 (63.6%) and 3 (27.3%) malignant PTs were identified as Claudin-low and Basal-like, respectively. Finally, we observed that the previously described PAM50 risk of relapse prognostic score better predicted outcome in FTs than the morphological classification, even within PTs-only. Our results suggest that classification of FTs using gene expression-based data is feasible and might provide clinically useful biological and prognostic information.

Project description:Background: The preoperative diagnosis of phyllodes tumors (PTs) of the breast is critical to appropriate surgical treatment. However, reliable differentiation between PT and fibroadenoma (FA) remains difficult in daily clinical practice. The purpose of this study was to investigate the utility of breast MRI texture analysis for differentiating PTs from FAs. Materials and Methods: Forty-two PTs and 42 FAs were enrolled in this retrospective study. Clinical and conventional MRI features (CCMF) and MRI texture analysis were used to distinguish between PT and FA. Texture features were extracted from the axial short TI inversion recovery T2-weighted (T2W-STIR), T1-weighted pre-contrast, and two contrast-enhanced series (first contrast and third contrast). The Mann-Whitney U test was used to select statistically significant features of texture analysis and CCMF. Using a linear discriminant analysis, the most discriminative features were determined from statistically significant features. The K-nearest neighbor classifier and ROC curve were applied to evaluate the diagnostic performance. Results: With a higher classification accuracy (89.3%) and an AUC of 0.89, the texture features on T2W-STIR outperformed the texture features on other MRI sequences and CCMF. The AUC of the combination of CCMF with texture features on T2W-STIR was significantly higher than that of CCMF or texture features on T2W-STIR alone (p < 0.05). Based on the result of the classification accuracy (95.2%) and AUC (0.95), the diagnostic performance of the combination strategy performed better than texture features on T2W-STIR or CCMF separately. Conclusions: Texture features on T2W-STIR showed better diagnostic performance compared to CCMF for the distinction between PTs and FAs. After further validation of multi-institutional large datasets, MRI-based texture features may become a potential biomarker and be a useful medical decision tool in clinical trials having patients with breast fibroepithelial neoplasms.

Dataset Information

MED12 somatic mutations in fibroadenomas and phyllodes tumours of the breast.

Publications

MED12 somatic mutations in fibroadenomas and phyllodes tumours of the breast.

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