1. Genomic landscapes of breast fibroepithelial tumors
- Author
-
Nur Diyana Md Nasir, Chow Yin Wong, Ioana Cutcutache, Wei Sean Yong, Buhari Shaik Ahmad, Mikael Hartman, Giovani Claresta Wijaya, Bernice Huimin Wong, Thomas C. Putti, Ching Wan Chan, Bin Tean Teh, Sucharita Dey, Philip Iau, Ley Moy Ng, Patrick Tan, Preetha Madhukumar, Steven G. Rozen, Su Ting Tay, John R. McPherson, Jing Tan, Jing Quan Lim, Benita Kiat Tee Tan, Zhimei Li, Cedric Chuan Young Ng, Wai Jin Tan, Weng Khong Lim, Swe Swe Myint, Kong Wee Ong, Jason Yongsheng Chan, Choon Kiat Ong, Gregory Poore, Veronique Kiak Mien Tan, Puay Hoon Tan, Anthony Tang, Saranya Thangaraju, Sanjanaa Nagarajan, Vikneswari Rajasegaran, Aye Aye Thike, and Dachuan Huang
- Subjects
Adult ,Adolescent ,Receptors, Retinoic Acid ,Filamins ,Loss of Heterozygosity ,Breast Neoplasms ,Biology ,medicine.disease_cause ,MED12 ,Young Adult ,Germline mutation ,Breast cancer ,Phyllodes Tumor ,Genetics ,medicine ,Humans ,Exome ,Genetic Predisposition to Disease ,Exome sequencing ,Aged ,Mediator Complex ,Base Sequence ,Retinoic Acid Receptor alpha ,High-Throughput Nucleotide Sequencing ,Phyllodes tumor ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Fibroadenoma ,Neoplasm Proteins ,DNA-Binding Proteins ,HEK293 Cells ,Mutation ,Cancer research ,Female ,Carcinogenesis ,Genome-Wide Association Study - 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.
- Published
- 2015