SF3B1 mutations constitute a novel therapeutic target in breast cancer. Issue 4 (22nd December 2014)

• Record Type: Journal Article
• Authors: Maguire, Sarah L; Leonidou, Andri; Wai, Patty; Marchiò, Caterina; Ng, Charlotte KY; Sapino, Anna; Salomon, Anne‐Vincent; Reis‐Filho, Jorge S; Weigelt, Britta; Natrajan, Rachael C
• Is Part Of: Journal of pathology. Volume 235:Issue 4(2015)
• Page Start: 571
• Page End: 580
• Publication Date: 2014-12-22
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4483
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main" id="path4483-abs-0001"> <title>Abstract</title> <p id="path4483-para-0001">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 <italic>SF3B1</italic> gene, which were found in 1.8% of unselected breast cancers. <italic>SF3B1</italic> mutations were significantly associated with ER‐positive disease, <italic>AKT1</italic> 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 <italic>SF3B1</italic> K700E mutation. RNA sequencing identified differentially spliced events expressed in tumours with <italic>SF3B1</italic> mutations including the protein coding genes <italic>TMEM14C</italic>, <italic>RPL31</italic>, <italic>DYNL11</italic>, <italic>UQCC</italic>, and <italic>ABCC5</italic>, and the long non‐coding RNA <italic>CRNDE</italic>. Moreover, <italic>SF3B1</italic> 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, <italic>SF3B1</italic> mutations result in alternative splicing events, and may constitute drivers and a novel therapeutic target in a subset of breast cancers. © 2014 The Authors. <italic>The Journal of Pathology</italic> published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.</p> </abstract>