Abstract
Breast fibroepithelial tumors comprise a heterogeneous spectrum of pathological entities, from benign fibroadenomas to malignant phyllodes tumors1. Although MED12 mutations have been frequently found in fibroadenomas and phyllodes tumors2,3,4,5,6,7, 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.
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Acknowledgements
This work was supported in part by funding from the Singapore National Medical Research Council (NMRC/STAR/0006/2009), the Singapore National Cancer Centre Research Fund, the Lee Foundation, the Tanoto Foundation and the Verdant Foundation. We thank the Duke–National University of Singapore Genome Biology Facility for sequencing services rendered, as well as the Advanced Molecular Pathology Laboratory, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, for providing laser-capture microdissection resources and the SingHealth Tissue Repository for frozen tissue samples.
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J.T., C.K.O., W.K.L., S.G.R., P.T., P.H.T. and B.T.T. conceived the study. S.G.R., P.T., P.H.T. and B.T.T. directed the study and supervised the research. J.R.M., W.K.L., I.C., S.N., J.Q.L., S.T., S.D., L.M.N. and G.P. performed the bioinformatics analysis. A.A.T., N.D.M.N., T.C.P., B.S.A., P.I., C.W.C., A.P.H.T., W.S.Y., P.M., G.H.H., V.K.M.T., C.Y.W., M.H., K.W.O. and B.K.T.T. collected tumor specimens, confirmed histopathology findings and interpreted the clinical data. S.S.M. was involved in sample preparation. C.C.Y.N., V.R., Z.L., G.C.W., D.H., B.H.W. and S.T.T. performed whole-exome sequencing, Sanger sequencing and targeted sequencing. J.T., C.K.O., W.K.L., S.G.R., P.T., P.H.T. and B.T.T. wrote the manuscript, with the assistance and final approval of all authors.
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Supplementary Text and Figures
Supplementary Figures 1–10, Supplementary Tables 1, 2, 4, 6–8 and 10. (PDF 3810 kb)
Supplementary Table 3
List of candidate somatic mutations identified from whole-exome sequencing of 22 cases of phyllodes tumor. (XLSX 54 kb)
Supplementary Table 5
Somatic mutations detected by targeted sequencing in 100 fibroepithelial tumors. (XLSX 41 kb)
Supplementary Table 9
List of synonymous mutations identified from whole-exome sequencing of 22 cases of phyllodes tumors. (XLSX 19 kb)
Supplementary Data Set 1
Clonality analysis data. (ZIP 1005 kb)
Supplementary Data Set 2
Images of copy number variants in 100 fibroepithelial tumors. (ZIP 10622 kb)
Supplementary Data Set 3
Genome browser snapshots for candidate variants in targeted sequencing data. (ZIP 4564 kb)
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Tan, J., Ong, C., Lim, W. et al. Genomic landscapes of breast fibroepithelial tumors. Nat Genet 47, 1341–1345 (2015). https://doi.org/10.1038/ng.3409
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DOI: https://doi.org/10.1038/ng.3409
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