title: The genetics of splicing in neuroblastoma.
abstract: Regulation of mRNA splicing, a critical and tightly regulated cellular function, underlies the majority of proteomic diversity and is frequently disrupted in disease. Using an integrative genomics approach, we combined both genomic data and exon-level transcriptome data in two somatic tissues (cerebella and peripheral ganglia) from a transgenic mouse model of neuroblastoma, a tumor that arises from the peripheral neural crest. Here, we describe splicing quantitative trait loci associated with differential splicing across the genome that we use to identify genes with previously unknown functions within the splicing pathway and to define de novo intronic splicing motifs that influence splicing from hundreds of bases away. Our results show that these splicing motifs represent sites for functional recurrent mutations and highlight novel candidate genes in human cancers, including childhood neuroblastoma.
  
  
  CONCLUSIONS
  Somatic mutations with predictable downstream effects are largely relegated to coding regions, which comprise less than 2% of the human genome. Using an unbiased in vivo analysis of a mouse model of neuroblastoma, we have identified intronic splicing motifs that translate into sites for recurrent somatic mutations in human cancers.
authors: Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, California. Department of Neurology, University of California, San Francisco, San Francisco, California. Department of Neurosurgery, University of California, San Francisco, San Francisco, California.
authors: Justin
authors: J
authors: Chen
authors: Department of Neurology, University of California, San Francisco, San Francisco, California. Department of Neurosurgery, University of California, San Francisco, San Francisco, California.
authors: Christopher S
authors: CS
authors: Hackett
authors: Program in Bioinformatics, Boston University, Boston, Massachusetts. Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
authors: Shile
authors: S
authors: Zhang
authors: Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
authors: Young K
authors: YK
authors: Song
authors: Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
authors: Robert J A
authors: RJ
authors: Bell
authors: Department of Neurology, University of California, San Francisco, San Francisco, California. Department of Neurosurgery, University of California, San Francisco, San Francisco, California. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
authors: Annette M
authors: AM
authors: Molinaro
authors: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. Institute for Cancer Research, Oslo, Norway.
authors: David A
authors: DA
authors: Quigley
authors: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
authors: Allan
authors: A
authors: Balmain
authors: Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California. Department of Bioengineering, University of Illinois, Urbana-Champaign, Urbana, Illinois. Department of Physics, University of Illinois, Urbana-Champaign, Urbana, Illinois.
authors: Jun S
authors: JS
authors: Song
authors: Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
authors: Joseph F
authors: JF
authors: Costello
authors: Department of Pediatrics, University of California, San Francisco, San Francisco, California.
authors: W Clay
authors: WC
authors: Gustafson
authors: Mouse Cancer Genetics Program, Center for Advanced Preclinical Research, National Cancer Institute, Frederick, Maryland.
authors: Terry
authors: T
authors: Van Dyke
authors: Institute for Human Genetics, University of California, San Francisco, San Francisco, California. Department of Dermatology, University of California, San Francisco, San Francisco, California. Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California.
authors: Pui-Yan
authors: PY
authors: Kwok
authors: Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
authors: Javed
authors: J
authors: Khan
authors: Department of Neurology, University of California, San Francisco, San Francisco, California. Department of Neurosurgery, University of California, San Francisco, San Francisco, California. Department of Pediatrics, University of California, San Francisco, San Francisco, California. waweiss@gmail.com.
authors: William A
authors: WA
authors: Weiss
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002531:Cerebellum / Q000378:metabolism; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D055106:Genome-Wide Association Study; D023281:Genomics; D007438:Introns; D051379:Mice; D009154:Mutation; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism; D059372:Nucleotide Motifs; D040641:Quantitative Trait Loci; D059368:RNA Isoforms; D012326:RNA Splicing; D013045:Species Specificity; D017783:Superior Cervical Ganglion / Q000378:metabolism
chemical_list: D059368:RNA Isoforms
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