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Ref Type Journal Article
PMID (25424858)
Authors Maguire SL, Leonidou A, Wai P, Marchiò C, Ng CK, Sapino A, Salomon AV, Reis-Filho JS, Weigelt B, Natrajan RC
Title SF3B1 mutations constitute a novel therapeutic target in breast cancer.
Journal The Journal of pathology
Vol 235
Issue 4
Date 2015 Mar
URL
Abstract Text 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 SF3B1 K700E 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 RNA CRNDE. 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
SF3B1 A633V missense unknown SF3B1 A633V lies within HEAT repeat 3 of the Sf3b1 protein (UniProt.org). A633V has been identified in the scientific literature (PMID: 25768983, PMID: 25424858), but has not been biochemically characterized and therefore, its effect on Sf3b1 protein function is unknown (PubMed, Aug 2020).
SF3B1 D781E missense unknown SF3B1 D781E lies within HEAT repeat 6 of the Sf3b1 protein (UniProt.org). D781E has been identified in sequencing studies (PMID: 25424858, PMID: 26565915), but has not been biochemically characterized and therefore, its effect on Sf3b1 protein function is unknown (PubMed, Aug 2020).
SF3B1 N626D missense unknown SF3B1 N626D lies within HEAT repeat 3 of the Sf3b1 protein (UniProt.org). N626D has been identified in sequencing studies (PMID: 25424858, PMID: 27771989, PMID: 23070040), but has not been biochemically characterized and therefore, its effect on Sf3b1 protein function is unknown (PubMed, Aug 2020).
SF3B1 Y765C missense unknown SF3B1 Y765C lies within HEAT repeat 6 of the Sf3b1 protein (UniProt.org). Y765C has been identified in the scientific literature (PMID: 25768983, PMID: 25424858), but has not been biochemically characterized and therefore, its effect on Sf3b1 protein function is unknown (PubMed, Aug 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SF3B1 K700E pancreatic cancer sensitive Spliceostatin A Preclinical Actionable In a preclinical study, Spliceostatin A inhibited survival of pancreatic cancer cells harboring SF3B1 K700E in culture (PMID: 25424858). 25424858
SF3B1 K666N endometrial cancer sensitive Spliceostatin A Preclinical Actionable In a preclinical study, Spliceostatin A inhibited survival of endometrial cancer cells harboring SF3B1 K666N in culture (PMID: 25424858). 25424858