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2015 ; 5
(4
): 380-95
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The genetics of splicing in neuroblastoma
#MMPMID25637275
Chen J
; Hackett CS
; Zhang S
; Song YK
; Bell RJ
; Molinaro AM
; Quigley DA
; Balmain A
; Song JS
; Costello JF
; Gustafson WC
; Van Dyke T
; Kwok PY
; Khan J
; Weiss WA
Cancer Discov
2015[Apr]; 5
(4
): 380-95
PMID25637275
show ga
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.
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