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Nat Genet. 2015 Nov;47(11):1341-5. doi: 10.1038/ng.3409. Epub 2015 Oct 5.

Genomic landscapes of breast fibroepithelial tumors.

Tan J1,2, Ong CK1,2, Lim WK1,2, Ng CC1,2, Thike AA3, Ng LM4, Rajasegaran V1,2, Myint SS1,2, Nagarajan S1,2, Thangaraju S1,2, Dey S4, Nasir ND3, Wijaya GC1,2, Lim JQ1,2, Huang D1,2, Li Z1,2, Wong BH1, Chan JY5, McPherson JR2, Cutcutache I2, Poore G6, Tay ST2, Tan WJ3, Putti TC7, Ahmad BS8, Iau P8, Chan CW8, Tang AP8, Yong WS9,10,11, Madhukumar P9,10,11, Ho GH9,10,11, Tan VK9,10,11, Wong CY9,10,11, Hartman M8,12,13, Ong KW9,10,11, Tan BK9,10,11, Rozen SG2, Tan P2,4,14, Tan PH3, Teh BT1,2,4,15.

Author information

1
Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.
2
Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
3
Department of Pathology, Singapore General Hospital, Singapore.
4
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
5
Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
6
Department of Biomedical Engineering, Duke University, Durham, North Carolina, USA.
7
Department of Pathology, National University of Singapore Yong Loo Lin School of Medicine, Singapore.
8
Department of Surgery, National University Hospital, Singapore.
9
Department of Surgical Oncology, National Cancer Center Singapore, Singapore.
10
Department of General Surgery, Singapore General Hospital, Singapore.
11
SingHealth Duke-National University of Singapore Breast Centre, Singapore.
12
Saw Swee Hock School of Public Health, National University of Singapore, Singapore.
13
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
14
Genome Institute of Singapore, Singapore.
15
Institute of Molecular and Cellular Biology, Singapore.

Abstract

Breast fibroepithelial tumors comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant phyllodes tumors. Although MED12 mutations have been frequently found in fibroadenomas and phyllodes tumors, the landscapes of genetic alterations across the fibroepithelial tumor spectrum remain unclear. Here, by performing exome sequencing of 22 phyllodes tumors followed by targeted sequencing of 100 breast fibroepithelial tumors, we observed three distinct somatic mutation patterns. First, we frequently observed MED12 and RARA mutations in both fibroadenomas and phyllodes tumors, emphasizing the importance of these mutations in fibroepithelial tumorigenesis. Second, phyllodes tumors exhibited mutations in FLNA, SETD2 and KMT2D, suggesting a role in driving phyllodes tumor development. Third, borderline and malignant phyllodes tumors harbored additional mutations in cancer-associated genes. RARA mutations exhibited clustering in the portion of the gene encoding the ligand-binding domain, functionally suppressed RARA-mediated transcriptional activation and enhanced RARA interactions with transcriptional co-repressors. This study provides insights into the molecular pathogenesis of breast fibroepithelial tumors, with potential clinical implications.

PMID:
26437033
DOI:
10.1038/ng.3409
[Indexed for MEDLINE]

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