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SF3B1 mutations constitute a novel therapeutic target in breast cancer

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Maguire, S. L., Leonidou, A., Wai, P., Marchio, C., Ng, C. K. Y., Sapino, A., Salomon, A. V., Reis, J. S., Weigelt, B., Natrajan, R. C. (2015) SF3B1 mutations constitute a novel therapeutic target in breast cancer. JOURNAL OF PATHOLOGY, 235 (4). pp. 571-580. ISSN 0022-3417

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Abstract

Mutations in genes encoding proteins involved in RNA splicing have been found to occur at relatively high frequencies in several tumour types including myelodysplastic syndromes, chronic lymphocytic leukaemia, uveal melanoma, and pancreatic cancer, and at lower frequencies in breast cancer. To investigate whether dysfunction in RNA splicing is implicated in the pathogenesis of breast cancer, we performed a re-analysis of published exome and whole genome sequencing data. This analysis revealed that mutations in spliceosomal component genes occurred in 5.6% of unselected breast cancers, including hotspot mutations in the SF3B1 gene, which were found in 1.8% of unselected breast cancers. SF3B1 mutations were significantly associated with ER-positive disease, AKT1 mutations, and distinct copy number alterations. Additional profiling of hotspot mutations in a panel of special histological subtypes of breast cancer showed that 16% and 6% of papillary and mucinous carcinomas of the breast harboured the SF3B1K700E mutation. RNA sequencing identified differentially spliced events expressed in tumours with SF3B1 mutations including the protein coding genes TMEM14C, RPL31, DYNL11, UQCC, and ABCC5, and the long non-coding RNACRNDE. Moreover, SF3B1 mutant cell lines were found to be sensitive to the SF3b complex inhibitor spliceostatin A and treatment resulted in perturbation of the splicing signature. Albeit rare, SF3B1 mutations result in alternative splicing events, and may constitute drivers and a novel therapeutic target in a subset of breast cancers. (c) 2014 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Item Type: Article
Authors (ICR Faculty only): Natrajan, Rachael
All Authors: Maguire, S. L., Leonidou, A., Wai, P., Marchio, C., Ng, C. K. Y., Sapino, A., Salomon, A. V., Reis, J. S., Weigelt, B., Natrajan, R. C.
Additional Information: ISI Document Delivery No.: CB5OQ Times Cited: 0 Cited Reference Count: 32 Maguire, Sarah L. Leonidou, Andri Wai, Patty Marchio, Caterina Ng, Charlotte K. Y. Sapino, Anna Salomon, Anne-Vincent Reis-Filho, Jorge S. Weigelt, Britta Natrajan, Rachael C. Breast Cancer Campaign; Breakthrough Breast Cancer; CRUK PhD studentship; Breast Cancer Campaign Career Development Fellowship; AIRC [MGAF13310]; NHS [IG 10787] This study was funded by Breast Cancer Campaign and Breakthrough Breast Cancer. AL is funded by a CRUK PhD studentship. RN is the recipient of a Breast Cancer Campaign Career Development Fellowship. CM is funded by AIRC (MGAF13310). We acknowledge NHS funding to the NIHR Biomedical Research Centre and AIRC (IG 10787). 0 WILEY-BLACKWELL HOBOKEN J PATHOL
Uncontrolled Keywords: breast cancer next-generation sequencing drivers SF3B1 alternative splicing spliceostatin A CHRONIC LYMPHOCYTIC-LEUKEMIA PRE-MESSENGER-RNA MICROPAPILLARY CARCINOMAS DUCTAL CARCINOMAS SPLICING FACTOR UVEAL MELANOMA TUMORS GENES PATHWAY MYELODYSPLASIA Oncology Pathology
Research teams: ICR divisions > Breast Cancer Research > Functional Genomics
Depositing User: Users 11 not found.
Date Deposited: 20 Mar 2015 10:21
Last Modified: 24 Mar 2015 09:39
URI: http://publications.icr.ac.uk/id/eprint/13979

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