Exome sequencing identifies highly recurrent MED12 somatic mutations in breast fibroadenoma

被引：147

作者：

Lim, Weng Khong ^{[1
,2
]}

Ong, Choon Kiat ^{[1
,2
]}

Tan, Jing ^{[1
,2
]}

Thike, Aye Aye ^{[3
]}

Ng, Cedric Chuan Young ^{[1
,2
]}

Rajasegaran, Vikneswari ^{[1
,2
]}

Myint, Swe Swe ^{[1
,2
]}

Nagarajan, Sanjanaa ^{[1
,2
]}

Nasir, Nur Diyana Md ^{[3
]}

McPherson, John R. ^{[4
]}

Cutcutache, Ioana ^{[4
]}

Poore, Gregory ^{[5
]}

Tay, Su Ting ^{[2
]}

Ooi, Wei Siong ^{[6
]}

Tan, Veronique Kiak Mien ^{[7
]}

Hartman, Mikael ^{[8
]}

Ong, Kong Wee ^{[7
]}

Tan, Benita K. T. ^{[9
]}

Rozen, Steven G. ^{[4
]}

Tan, Puay Hoon ^{[3
]}

Tan, Patrick ^{[2
,10
,11
]}

Teh, Bin Tean ^{[1
,2
,11
]}

机构：

[1] Natl Canc Ctr, Div Med Sci, Lab Canc Epigenome, Singapore, Singapore

[2] Duke Natl Univ Singapore, Grad Sch Med, Div Canc & Stem Cell Biol, Singapore, Singapore

[3] Singapore Gen Hosp, Dept Pathol, Singapore, Singapore

[4] Duke NUS Grad Med Sch, Div Neurosci & Behav Disorders, Singapore, Singapore

[5] Duke Univ, Dept Biomed Engn, Durham, NC 27706 USA

[6] Natl Canc Ctr, Dept Med Oncol, Singapore, Singapore

[7] Natl Canc Ctr, Div Surg Oncol, Singapore, Singapore

[8] Natl Univ Singapore Hosp, Dept Surg, Singapore, Singapore

[9] Singapore Gen Hosp, Dept Gen Surg, Singapore, Singapore

[10] Genome Inst Singapore, Singapore, Singapore

[11] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore 117548, Singapore

来源：

NATURE GENETICS | 2014年 / 46卷 / 08期

基金：

英国医学研究理事会;

关键词：

PHYLLODES TUMOR; CANCER; RISK; GENE; LANDSCAPE;

D O I：

10.1038/ng.3037

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：877 / 880

页数：4

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