Distribution of MED12 mutations in fibroadenomas and phyllodes tumors of the breast—implications for tumor biology and pathological diagnosis

Abstract

Somatic mutations in exon 2 of MED12 have been described in benign and malignant smooth muscle cell tumors suggesting a functional role in these neoplasms. Recently fibroadenomas of the breast were also reported to harbor MED12 mutations. Hence, we explored MED12 mutations in fibroepithelial tumors of the breast, histological subtypes of fibroadenomas and phyllodes tumors, to validate and extend previous efforts. Using conventional Sanger sequencing, we profiled 39 cases of fibroepithelial breast tumors comprising classic histological subtypes of fibroadenomas as well as benign and malignant phyllodes tumors for mutations in exon 2 of MED12. MED12 mutations were detected in 60% of all tumor samples with the majority being missense mutations affecting codon 44. Additionally, we report novel in-frame deletions that have not been described previously. Sixty-two percent of the fibroadenomas harbored mutated MED12 with intracanalicular fibroadenomas being the most frequently mutated histological subtype (82%). Of note, 8/11 of benign phyllodes tumors had MED12 mutations while only 1/5 of malignant phyllodes tumors showed mutations in exon 2 of MED12. In conclusion, we confirm the frequent occurrence of MED12 mutations in fibroadenomas, provide evidence that most intracanalicular fibroadenomas closely resembling benign phyllodes as well as benign phyllodes tumors harbor MED12 mutations, and conclude that MED12 mutations in malignant phyllodes tumors appear to be relatively rare.

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

“…We found that the frequency of MED12 mutant tumors is higher in benign than in intermediate/malignant PT although the difference is not statistically significant. Similar results have been reported elsewhere [14][15][16][17][18] and all these reports Table 1), suggesting that MED12 mutation is not implicated in the pathogenesis of about two-thirds of malignant PTs. However, the genetic change(s) responsible for the pathogenesis of malignant PTs remains to be elucidated.…”

“…Similar results have been reported by other investigators [16][17][18]. The pathogenesis of FAs and PTs remains largely unknown but these observations seem to indicate a significant involvement of MED12 mutation in their pathogenesis.…”

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

“…The frequency of MED12 somatic mutations reported ranges from 45% to 80%, not significantly different between fibroadenomas and phyllodes tumours, although some authors report a lower frequency in malignant phyllodes tumours10 11 while other studies show no significant difference among phyllodes tumours of different grades 2 12. In uterine leiomyomas, mutations of MED12 are common, but are rare in its malignant counterpart the leiomyosarcoma 13–15.…”

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

“…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.…”