Exome sequencing identifies highly recurrent MED12 somatic mutations in breast fibroadenoma

Abstract

Fibroadenomas are the most common breast tumors in women under 30 (refs. 1,2). Exome sequencing of eight fibroadenomas with matching whole-blood samples revealed recurrent somatic mutations solely in MED12, which encodes a Mediator complex subunit. Targeted sequencing of an additional 90 fibroadenomas confirmed highly frequent MED12 exon 2 mutations (58/98, 59%) that are probably somatic, with 71% of mutations occurring in codon 44. Using laser capture microdissection, we show that MED12 fibroadenoma mutations are present in stromal but not epithelial mammary cells. Expression profiling of MED12-mutated and wild-type fibroadenomas revealed that MED12 mutations are associated with dysregulated estrogen signaling and extracellular matrix organization. The fibroadenoma MED12 mutation spectrum is nearly identical to that of previously reported MED12 lesions in uterine leiomyoma but not those of other tumors. Benign tumors of the breast and uterus, both of which are key target tissues of estrogen, may thus share a common genetic basis underpinned by highly frequent and specific MED12 mutations.

The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans

“…Our findings are also of potential clinical interest, as the human CKM is implicated in tumorigenesis (Firestein et al 2008;Donner et al 2010;Mäkinen et al 2011;Lim et al 2014). Loss of MED12 causes cellular resistance to chemotherapeutic agents that inhibit activated BRAF, the human ERK kinase kinase (Shalem et al 2014); this suggests that MED12 represses EGFR signaling downstream of BRAF, in line with our findings for the C. elegans CKM.…”

“…Loss of MED12 causes cellular resistance to chemotherapeutic agents that inhibit activated BRAF, the human ERK kinase kinase (Shalem et al 2014); this suggests that MED12 represses EGFR signaling downstream of BRAF, in line with our findings for the C. elegans CKM. Furthermore, recurrent MED12 mutations are implicated in uterine leiomyomas and breast fibroadenomas (Mäkinen et al 2011;Lim et al 2014;Mittal et al 2015), but the pathogenic mechanisms of these mutations have not been fully elucidated. Investigation of these mutations using the C. elegans vulva development paradigm may provide insight into their mode of action.…”

Med12 gain-of-function mutation causes leiomyomas and genomic instability

“…These results indicate that Med12 mutations can cause the genomic instability frequently seen in human leiomyomas. Recurrent human MED12 exon 2 mutations have been associated with benign tumors such as uterine leiomyomas (7) and breast fibroadenomas (15); however, their etiology, genetic mechanism of action, and role in genomic instability are unknown. We generated mouse models with Med12 loss of function and the most common human MED12 c.131G>A variant and studied their effects in mouse uteri.…”

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].…”