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.
Weng Khong Lim1,2,12, Choon Kiat Ong1,2,12, Jing Tan1,2,12, Aye Aye Thike3, Cedric Chuan Young Ng1,2, Vikneswari Rajasegaran1,2, Swe Swe Myint1,2, Sanjanaa Nagarajan1,2, Nur Diyana Md Nasir3, John R McPherson4, Ioana Cutcutache4, Gregory Poore5, Su Ting Tay2, Wei Siong Ooi6, Veronique Kiak Mien Tan7, Mikael Hartman8, Kong Wee Ong7, Benita K T Tan9, Steven G Rozen4, Puay Hoon Tan3, Patrick Tan2,10,11 & Bin Tean Teh1,2,11
1Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore
2Division of Cancer and Stem Cell Biology, Duke–National University of Singapore (NUS) Graduate Medical School, Singapore.
3Department of Pathology, Singapore General Hospital, Singapore.
4Division of Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore. 5Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA. 6Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
7Department of Surgical Oncology, National Cancer Centre Singapore, Singapore.
8Department of Surgery, National University Hospital, Singapore.
9Department of General Surgery, Singapore General Hospital, Singapore.
10Genome Institute of Singapore, Singapore.
11Cancer Science Institute of Singapore, National University of Singapore, Singapore.
12These authors contributed equally to this work. Correspondence should be addressed to B.T.T.
(teh.bin.tean[at]singhealth.com.sg), P.T. (gmstanp[at]duke-nus.edu.sg), P.H.T. (tan.puay.hoon[at]sgh.com.sg) or S.G.R. (steve.rozen[at]duke-nus.edu.sg).