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

Abstract

We aimed to analyze MED12 mutation in fibroadenomas (FAs) and phyllodes tumors (PTs) of the breast, which are closely related and consist of epithelial and stromal components. Targeted deep-sequencing using next-generation sequencing was performed in FAs (n = 58) and PTs (n = 27). The frequency of MED12 mutant tumors was significantly higher (P = 0.016) in PTs (74.1 %) than in FAs. (46.6 %). As for FAs, this frequency was significantly higher (P = 0.001) for intracanalicular type (69.0 %) than for other histological subtypes such as pericanalicular, organoid, and mastopathic types (24.1 %). Laser microdissection study revealed that stromal cells, but not epithelial cells, harbored MED12 mutations in both FAs and PTs. MED12 mutation is implicated in the pathogenesis of both FAs and PTs. The similarly high frequency of MED12 mutation in intracanalicular type FAs suggests that they are most closely related to PTs. It is thus speculated that FAs with MED12 mutation are more likely to progress to PTs.

Molecular insights into paediatric breast fibroepithelial tumours

“…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. 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%).…”

“…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.…”

“…The significance of this finding is uncertain, especially as only 10 cases among the entire cohort displayed mitoses. Interestingly, although fibroadenomas with a higher stromal mitotic count may be associated with an increased risk of recurrence, some studies have found conversely that phyllodes tumours with MED12 mutations have a lower risk of recurrence . Also, another study reported that stromal mitotic activity in paediatric fibroadenomas can be substantial, ranging up to seven per 10 high‐power fields, and caution against overdiagnosing phyllodes tumours …”

“…For a long time, the pathogenetic mechanisms behind the growth of these tumours remained poorly understood, with sometimes conflicting results from different studies . However, in recent years, different groups have demonstrated the presence of recurrent mutations in the MED12 gene in fibroadenomas, particularly in codon 44 of exon 2 . While these studies were performed on a range of fibroepithelial tumours from fibroadenomas to malignant phyllodes tumours and throughout the age spectrum, there is a paucity of studies that focus only upon fibroepithelial tumours in the paediatric age group.…”

Myxoid fibroadenomas differ from conventional fibroadenomas: a hypothesis‐generating study

“…Here, we demonstrate that, unlike conventional FAs, >70% of which harbour MED12 mutations in the stromal (i.e. mesenchymal) components, non‐Carney complex‐related MFAs lack MED12 mutations, and no somatic mutations affecting the 410 cancer genes included in our sequencing assay are present at high mutant allele fractions. Moreover, apart from the PRKAR1A mutation in MFA6, selected pathogenic mutations affecting known cancer genes were found to be restricted to the epithelial components of these lesions.…”