Comprehensive identification of mRNA splicing-altering somatic intronic variants in human cancers = mRNA 스플라이싱에 영향을 미치는 암 특이적인 인트론 돌연변이 연구

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A substantial fraction of somatic mutations including retrotransposition alters cancer-associated genes through abnormal splicing. Although such mutations have been characterized in human cancers, previous studies have been limited to those within splice sites and exons due to a lack of sufficient number of tumor samples profiled by whole-genome- and RNA-sequencing. To portray a landscape of splicing-altering intronic variants, we analyzed thousands of tumor samples with both the profiling data. We identified ~700 somatic intronic mutations, with 40% of them occurring in deep introns. The deep intronic mutations resulted in abnormal splicing by altering core splicing code through activating cryptic donor/acceptor splice sites and polypriminde tracts and disrupting brachpoints. Notably, deep intronic mutations were enriched toward gain of splicing enhancers and/or loss of splicing silencers. We validated pseudo exon activation by CRISPR/Cas9-mediated deletion of splicing silencer motif. These mutations account for a large fraction of tumor suppressor disruption and show signatures of both positive and purifying selection on transcripts with nonsense-mediated decay (NMD)-sensitive premature termination codon (PTC).
Advisors
Choi, Jung Kyoonresearcher최정균researcher
Description
한국과학기술원 :바이오및뇌공학과,
Publisher
한국과학기술원
Issue Date
2018
Identifier
325007
Language
eng
Description

학위논문(박사) - 한국과학기술원 : 바이오및뇌공학과, 2018.8,[iii, 82 p. :]

Keywords

mRNA splicing▼aintron▼asomatic variants▼acancer; mRNA 스플라이싱▼a인트론▼a돌연변이▼a암

URI
http://hdl.handle.net/10203/264711
Link
http://library.kaist.ac.kr/search/detail/view.do?bibCtrlNo=828270&flag=dissertation
Appears in Collection
BiS-Theses_Ph.D.(박사논문)
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