Mutational analysis of <i>MED12</i> exon 2 in a spectrum of fibroepithelial tumours of the breast: implications for pathogenesis and histogenesis

Lien, Han‐Chung; Yang, Yu‐Cih; Jeng, Yung‐Ming

doi:10.1111/his.12764

Cited by 28 publications

(32 citation statements)

References 32 publications

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“…Our cohort of 43 tumours was composed largely of conventional fibroadenomas and juvenile fibroadenomas, with no phyllodes tumours available for comparison. We found MED12 mutations in 46.5% (20 of 43) of the tumours, which is at the lower range of the rates of MED12 mutations reported in fibroadenomas (21–85.7%) . This could be due to the significant proportion of juvenile fibroadenomas (17 of 43) in our cohort, which showed a lower frequency of MED12 mutations of 35% compared with 56% in the conventional fibroadenoma group.…”

Section: Discussioncontrasting

confidence: 71%

“…When comparing clinicopathological parameters of fibroadenomas with MED12 mutations versus those without, we found a significantly higher stromal mitotic count in tumours with MED12 mutations. Although other studies have found no significant relationship between the presence of MED12 mutations and stromal mitotic counts, these were performed on phyllodes tumours and not fibroadenomas . The significance of this finding is uncertain, especially as only 10 cases among the entire cohort displayed mitoses.…”

Section: Discussionmentioning

confidence: 80%

“…This is consistent with the findings of other studies which demonstrated a higher frequency of MED12 mutations in tumours with an intracanalicular growth pattern, which is usually not a feature of juvenile fibroadenomas. One study reported a higher incidence of MED12 mutations in juvenile fibroadenomas (52.6%). This study, however, used Sanger sequencing, which is a different platform from ours.…”

Section: Discussionmentioning

confidence: 99%

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Molecular insights into paediatric breast fibroepithelial tumours

et al. 2018

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Section: Discussioncontrasting

confidence: 71%

Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Molecular insights into paediatric breast fibroepithelial tumours

et al. 2018

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“…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 .…”

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confidence: 99%

Genomic landscapes of breast fibroepithelial tumors

et al. 2015

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Breast fibroepithelial tumors comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant phyllodes tumors. Although MED12 mutations have been frequently found in fibroadenomas and phyllodes tumors, the landscapes of genetic alterations across the fibroepithelial tumor spectrum remain unclear. Here, by performing exome sequencing of 22 phyllodes tumors followed by targeted sequencing of 100 breast fibroepithelial tumors, we observed three distinct somatic mutation patterns. First, we frequently observed MED12 and RARA mutations in both fibroadenomas and phyllodes tumors, emphasizing the importance of these mutations in fibroepithelial tumorigenesis. Second, phyllodes tumors exhibited mutations in FLNA, SETD2 and KMT2D, suggesting a role in driving phyllodes tumor development. Third, borderline and malignant phyllodes tumors harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the portion of the gene encoding 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.

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“…PTs are morphologically related to FAs, both being fibroepithelial tumours characterized by stroma and epithelium proliferations. Very recent reports, including our recent report, have shown MED12 exon 2 mutations in PTs . Because spindle tumour components are shared by SNB, in this study, we assessed the diagnostic use of MED12 exon 2 mutation in SNB, including MBCs, PTs, PNSs and fibromatoses.…”

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confidence: 95%

MED12 exon 2 mutation as a highly sensitive and specific marker in distinguishing phyllodes tumours from other spindle neoplasms of the breast

Lien

Yang

Jeng

2016

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Spindle neoplasms of the breast (SNB) primarily include metaplastic breast carcinoma (MBC), phyllodes tumour (PT), fibromatosis and primary nonspecific sarcoma (PNS). Mutations in MED12 exon 2 have been reported in PTs. Because spindle tumour components are shared by SNB, we assessed the diagnostic use of MED12 exon 2 mutation in SNB. We investigated MED12 exon 2 mutations in a total of 91 samples of SNB, including 49 PT cases that have been previously analysed. Mutations were identified using direct sequencing. MED12 exon 2 mutation was absent in all cases of MBC, fibromatosis and PNS, in contrast to the 71.4% positivity in PTs. MED12 mutations were identified in four of six previously diagnosed monophasic sarcomatous MCB cases, however, these four cases were revised as malignant PT based on additional bcl-2 staining, albeit very focal. Consistence in the MED12 mutational status between a paired core biopsy and a surgical specimen was observed in all 20 tested PT cases. In conclusion, we demonstrated the restriction of MED12 exon 2 mutation to PTs (73.6%, 39/53) and its absence in other SNB. MED12 exon 2 mutational analysis can be included in the differential diagnosis between PT and other SNB, especially with limited specimen where diagnostic clues are not evident.

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Mutational analysis of MED12 exon 2 in a spectrum of fibroepithelial tumours of the breast: implications for pathogenesis and histogenesis

Cited by 28 publications

References 32 publications

Molecular insights into paediatric breast fibroepithelial tumours

Molecular insights into paediatric breast fibroepithelial tumours

Genomic landscapes of breast fibroepithelial tumors

MED12 exon 2 mutation as a highly sensitive and specific marker in distinguishing phyllodes tumours from other spindle neoplasms of the breast

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