title: Transcriptome sequencing reveals potential mechanism of cryptic 3' splice site selection in SF3B1-mutated cancers.
abstract: Mutations in the splicing factor SF3B1 are found in several cancer types and have been associated with various splicing defects. Using transcriptome sequencing data from chronic lymphocytic leukemia, breast cancer and uveal melanoma tumor samples, we show that hundreds of cryptic 3' splice sites (3'SSs) are used in cancers with SF3B1 mutations. We define the necessary sequence context for the observed cryptic 3' SSs and propose that cryptic 3'SS selection is a result of SF3B1 mutations causing a shift in the sterically protected region downstream of the branch point. While most cryptic 3'SSs are present at low frequency (<10%) relative to nearby canonical 3'SSs, we identified ten genes that preferred out-of-frame cryptic 3'SSs. We show that cancers with mutations in the SF3B1 HEAT 5-9 repeats use cryptic 3'SSs downstream of the branch point and provide both a mechanistic model consistent with published experimental data and affected targets that will guide further research into the oncogenic effects of SF3B1 mutation.
authors.affiliation: Bioinformatics and Systems Biology, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: DeBoever
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Emanuela M
authors.initials: EM
authors.lastname: Ghia
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America; Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Shepard
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Laura
authors.initials: L
authors.lastname: Rassenti
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America; Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, California, United States of America; Institute for Genomic Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Christian L
authors.initials: CL
authors.lastname: Barrett
authors.affiliation: Institute for Genomic Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Kristen
authors.initials: K
authors.lastname: Jepsen
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America; Department of Medicine, University of California San Diego, La Jolla, California, United States of America; Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Catriona H M
authors.initials: CH
authors.lastname: Jamieson
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America; Department of Medicine, University of California San Diego, La Jolla, California, United States of America; Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Dennis
authors.initials: D
authors.lastname: Carson
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America; Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, California, United States of America; Institute for Genomic Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Frazer
mesh_terms: D006801:Humans; D009154:Mutation / Q000235:genetics* / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics*; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D017423:Sequence Analysis, RNA; D059467:Transcriptome / Q000235:genetics*
chemical_list: D010750:Phosphoproteins; D022821:RNA Splice Sites; D000072260:RNA Splicing Factors; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human