title: 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.
authors.affiliation: 1] Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. [2] Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore. [3].
authors.forename: Weng Khong
authors.initials: WK
authors.lastname: Lim
authors.affiliation: 1] Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. [2] Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore. [3].
authors.forename: Choon Kiat
authors.identifier: 0000000164024288
authors.initials: CK
authors.lastname: Ong
authors.affiliation: 1] Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. [2] Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore. [3].
authors.forename: Jing
authors.initials: J
authors.lastname: Tan
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore.
authors.forename: Aye Aye
authors.initials: AA
authors.lastname: Thike
authors.affiliation: 1] Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. [2] Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore.
authors.forename: Cedric Chuan Young
authors.initials: CC
authors.lastname: Ng
authors.affiliation: 1] Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. [2] Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore.
authors.forename: Vikneswari
authors.initials: V
authors.lastname: Rajasegaran
authors.affiliation: 1] Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. [2] Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore.
authors.forename: Swe Swe
authors.initials: SS
authors.lastname: Myint
authors.affiliation: 1] Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. [2] Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore.
authors.forename: Sanjanaa
authors.initials: S
authors.lastname: Nagarajan
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore.
authors.forename: Nur Diyana Md
authors.initials: ND
authors.lastname: Nasir
authors.affiliation: Division of Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore.
authors.forename: John R
authors.initials: JR
authors.lastname: McPherson
authors.affiliation: Division of Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Ioana
authors.initials: I
authors.lastname: Cutcutache
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.
authors.forename: Gregory
authors.identifier: 0000000234433715
authors.initials: G
authors.lastname: Poore
authors.affiliation: Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore.
authors.forename: Su Ting
authors.initials: ST
authors.lastname: Tay
authors.affiliation: Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
authors.forename: Wei Siong
authors.initials: WS
authors.lastname: Ooi
authors.affiliation: Department of Surgical Oncology, National Cancer Centre Singapore, Singapore.
authors.forename: Veronique Kiak Mien
authors.initials: VK
authors.lastname: Tan
authors.affiliation: Department of Surgery, National University Hospital, Singapore.
authors.forename: Mikael
authors.initials: M
authors.lastname: Hartman
authors.affiliation: Department of Surgical Oncology, National Cancer Centre Singapore, Singapore.
authors.forename: Kong Wee
authors.initials: KW
authors.lastname: Ong
authors.affiliation: Department of General Surgery, Singapore General Hospital, Singapore.
authors.forename: Benita K T
authors.initials: BK
authors.lastname: Tan
authors.affiliation: Division of Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Rozen
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore.
authors.forename: Puay Hoon
authors.initials: PH
authors.lastname: Tan
authors.affiliation: 1] Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore. [2] Genome Institute of Singapore, Singapore. [3] Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: 1] Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore. [2] Division of Cancer and Stem Cell Biology, Duke-National University of Singapore (NUS) Graduate Medical School, Singapore. [3] Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D003062:Codon; D004967:Estrogens / Q000235:genetics; D059472:Exome; D005091:Exons; D005109:Extracellular Matrix / Q000235:genetics; D005260:Female; D018226:Fibroadenoma / Q000235:genetics*; D006801:Humans; D056892:Mediator Complex / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D059467:Transcriptome; D055815:Young Adult
chemical_list: D003062:Codon; D004967:Estrogens; C460107:MED12 protein, human; D056892:Mediator Complex