title: Splicing Factor Mutations in Cancer.
abstract: Many cancers demonstrate aberrant splicing patterns that contribute to their development and progression. Recently, recurrent somatic mutations of genes encoding core subunits of the spliceosome have been identified in several different cancer types. These mutations are most common in hematologic malignancies like the myelodysplastic syndromes (MDS), acute myeloid leukemia, and chronic lymphocytic leukemia, but also in occur in several solid tumors at lower frequency. The most frequent mutations occur in SF3B1, U2AF1, SRSF2, and ZRSR2 and are largely exclusive of each other. Mutations in SF3B1, U2AF1, and SRSF2 acquire heterozygous missense mutations in specific codons, resembling oncogenes. ZRSR2 mutations include clear loss-of-function variants, a pattern more common to tumor suppressor genes. These splicing factors are associated with distinct clinical phenotypes and patterns of mutation in different malignancies. Mutations have both diagnostic and prognostic relevance. Splicing factor mutations appear to affect only a minority of transcripts which show little overlap by mutation type. How differences in splicing caused by somatic mutations of spliceosome subunits lead to oncogenesis is not clear and may involve different targets in each disease type. However, cells with mutated splicing machinery may be particularly vulnerable to further disruption of the spliceosome suggesting a novel strategy for the targeted therapy of cancers.
authors.affiliation: Division of Hematology and Oncology, UC San Diego Moores Cancer Center, La Jolla, CA, USA. rabejar@ucsd.edu.
authors.forename: Rafael
authors.initials: R
authors.lastname: Bejar
mesh_terms: D019337:Hematologic Neoplasms / Q000235:genetics; D006801:Humans; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D012326:RNA Splicing / Q000235:genetics*; D000072260:RNA Splicing Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000235:genetics / Q000502:physiology; D000068103:Serine-Arginine Splicing Factors / Q000235:genetics / Q000502:physiology; D000072668:Splicing Factor U2AF / Q000235:genetics / Q000502:physiology
chemical_list: D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010750:Phosphoproteins; D000072260:RNA Splicing Factors; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D012261:Ribonucleoproteins; C112491:SF3B1 protein, human; D000072668:Splicing Factor U2AF; C076753:U2AF1 protein, human; C484334:ZRSR2 protein, human; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors
keywords: Acute myeloid leukemia; Cancer; Myelodysplastic syndromes; Oncogenesis; SF3B1; SRSF2; Splicing; Stem cell; U2AF1; ZRSR2