Whole-exome and targeted amplicon sequencing of fibroadenomas.

Fibroadenomas are the most common breast tumors in women below 30. Exome sequencing of eight fibroadenomas with matching whole-blood revealed recurrent somatic mutations solely in MED12. Targeted prevalence sequencing of an additional 90 fibroadenomas confirmed a high frequency of MED12 exon 2 mutations (58/98, 59%) that are probably somatic, with 71% of mutations occurring in codon 44. Using laser capture microdissection (LCM) of frozen sections from four fibroadenomas, we showed that MED12 mutations are present in stromal but not epithelial mammary cells. Expression profiling of MED12-mutant and wild-type fibroadenomas revealed that MED12 mutations were associated with dysregulated estrogen signaling and extracellular matrix organization. The fibroadenoma MED12 mutation spectrum was nearly identical to previously reported MED12 lesions in uterine leiomyoma (UL) but not in other tumors, suggesting that benign tumors of the breast and uterus, both key target tissues of estrogen, may share a common genetic basis. Our results suggest that a major proportion of hormone-dependent benign tumors in distinct female tissues may be driven by a common underlying pathway, underpinned by remarkably frequent and specific MED12 mutations that are rare in other tissues.