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Cancer Discov. 2015 Apr;5(4):380-95. doi: 10.1158/2159-8290.CD-14-0892. Epub 2015 Jan 30.

The genetics of splicing in neuroblastoma.

Author information

1
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.
2
Department of Neurology, University of California, San Francisco, San Francisco, California. Department of Neurosurgery, University of California, San Francisco, San Francisco, California.
3
Program in Bioinformatics, Boston University, Boston, Massachusetts. Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
4
Oncogenomics Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland.
5
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.
6
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.
7
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California. Institute for Cancer Research, Oslo, Norway.
8
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California.
9
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.
10
Department of Pediatrics, University of California, San Francisco, San Francisco, California.
11
Mouse Cancer Genetics Program, Center for Advanced Preclinical Research, National Cancer Institute, Frederick, Maryland.
12
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.
13
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.

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.

SIGNIFICANCE:

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.

PMID:
25637275
PMCID:
PMC4390477
DOI:
10.1158/2159-8290.CD-14-0892
[Indexed for MEDLINE]
Free PMC Article
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