title: Genomic landscapes of breast fibroepithelial tumors.
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.
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Jing
authors.initials: J
authors.lastname: Tan
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Choon Kiat
authors.initials: CK
authors.lastname: Ong
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Weng Khong
authors.initials: WK
authors.lastname: Lim
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Cedric Chuan Young
authors.initials: CC
authors.lastname: Ng
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore.
authors.forename: Aye Aye
authors.initials: AA
authors.lastname: Thike
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Ley Moy
authors.initials: LM
authors.lastname: Ng
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Vikneswari
authors.initials: V
authors.lastname: Rajasegaran
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Swe Swe
authors.initials: SS
authors.lastname: Myint
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Sanjanaa
authors.initials: S
authors.lastname: Nagarajan
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Saranya
authors.initials: S
authors.lastname: Thangaraju
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Sucharita
authors.initials: S
authors.lastname: Dey
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore.
authors.forename: Nur Diyana Md
authors.initials: ND
authors.lastname: Nasir
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Giovani Claresta
authors.initials: GC
authors.lastname: Wijaya
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Jing Quan
authors.initials: JQ
authors.lastname: Lim
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Dachuan
authors.initials: D
authors.lastname: Huang
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.
authors.forename: Bernice Huimin
authors.initials: BH
authors.lastname: Wong
authors.affiliation: Department of Medical Oncology, National Cancer Centre Singapore, Singapore.
authors.forename: Jason Yong Sheng
authors.initials: JY
authors.lastname: Chan
authors.affiliation: Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: John R
authors.initials: JR
authors.lastname: McPherson
authors.affiliation: Division of Cancer and Stem Cell Biology, Duke-National University of Singapore 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.initials: G
authors.lastname: Poore
authors.affiliation: Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Su Ting
authors.initials: ST
authors.lastname: Tay
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore.
authors.forename: Wai Jin
authors.initials: WJ
authors.lastname: Tan
authors.affiliation: Department of Pathology, National University of Singapore Yong Loo Lin School of Medicine, Singapore.
authors.forename: Thomas Choudary
authors.initials: TC
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authors.affiliation: Department of Surgery, National University Hospital, Singapore.
authors.forename: Buhari Shaik
authors.initials: BS
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authors.affiliation: Department of Surgery, National University Hospital, Singapore.
authors.forename: Philip
authors.initials: P
authors.lastname: Iau
authors.affiliation: Department of Surgery, National University Hospital, Singapore.
authors.forename: Ching Wan
authors.initials: CW
authors.lastname: Chan
authors.affiliation: Department of Surgery, National University Hospital, Singapore.
authors.forename: Anthony P H
authors.initials: AP
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authors.affiliation: Department of Surgical Oncology, National Cancer Center Singapore, Singapore.|Department of General Surgery, Singapore General Hospital, Singapore.|SingHealth Duke-National University of Singapore Breast Centre, Singapore.
authors.forename: Wei Sean
authors.initials: WS
authors.lastname: Yong
authors.affiliation: Department of Surgical Oncology, National Cancer Center Singapore, Singapore.|Department of General Surgery, Singapore General Hospital, Singapore.|SingHealth Duke-National University of Singapore Breast Centre, Singapore.
authors.forename: Preetha
authors.initials: P
authors.lastname: Madhukumar
authors.affiliation: Department of Surgical Oncology, National Cancer Center Singapore, Singapore.|Department of General Surgery, Singapore General Hospital, Singapore.|SingHealth Duke-National University of Singapore Breast Centre, Singapore.
authors.forename: Gay Hui
authors.initials: GH
authors.lastname: Ho
authors.affiliation: Department of Surgical Oncology, National Cancer Center Singapore, Singapore.|Department of General Surgery, Singapore General Hospital, Singapore.|SingHealth Duke-National University of Singapore Breast Centre, Singapore.
authors.forename: Veronique Kiak Mien
authors.initials: VK
authors.lastname: Tan
authors.affiliation: Department of Surgical Oncology, National Cancer Center Singapore, Singapore.|Department of General Surgery, Singapore General Hospital, Singapore.|SingHealth Duke-National University of Singapore Breast Centre, Singapore.
authors.forename: Chow Yin
authors.initials: CY
authors.lastname: Wong
authors.affiliation: Department of Surgery, National University Hospital, Singapore.|Saw Swee Hock School of Public Health, National University of Singapore, Singapore.|Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Hartman
authors.affiliation: Department of Surgical Oncology, National Cancer Center Singapore, Singapore.|Department of General Surgery, Singapore General Hospital, Singapore.|SingHealth Duke-National University of Singapore Breast Centre, Singapore.
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authors.initials: KW
authors.lastname: Ong
authors.affiliation: Department of Surgical Oncology, National Cancer Center Singapore, Singapore.|Department of General Surgery, Singapore General Hospital, Singapore.|SingHealth Duke-National University of Singapore Breast Centre, Singapore.
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authors.initials: BK
authors.lastname: Tan
authors.affiliation: Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Rozen
authors.affiliation: Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Genome Institute of Singapore, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Department of Pathology, Singapore General Hospital, Singapore.
authors.forename: Puay Hoon
authors.initials: PH
authors.lastname: Tan
authors.affiliation: Laboratory of Cancer Epigenome, National Cancer Centre Singapore, Singapore.|Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Institute of Molecular and Cellular Biology, Singapore.
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005260:Female; D018226:Fibroadenoma / Q000235:genetics* / Q000378:metabolism; D064448:Filamins / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D057809:HEK293 Cells; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D003557:Phyllodes Tumor / Q000235:genetics* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C578663:FLNA protein, human; D064448:Filamins; C120898:KMT2D protein, human; C460107:MED12 protein, human; D056892:Mediator Complex; D009363:Neoplasm Proteins; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha