Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma

Feigin, Michael E., Garvin, Tyler, Bailey, Peter, Waddell, Nicola, Chang, David K., Kelley, David R., Shuai, Shimin, Gallinger, Steven, McPherson, John D., Grimmond, Sean M., Khurana, Ekta, Stein, Lincoln D., Biankin, Andrew V., Schatz, Michael C. and Tuveson, David A. (2017) Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma. Nature Genetics, 49 6: 825-833. doi:10.1038/ng.3861


Author Feigin, Michael E.
Garvin, Tyler
Bailey, Peter
Waddell, Nicola
Chang, David K.
Kelley, David R.
Shuai, Shimin
Gallinger, Steven
McPherson, John D.
Grimmond, Sean M.
Khurana, Ekta
Stein, Lincoln D.
Biankin, Andrew V.
Schatz, Michael C.
Tuveson, David A.
Title Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1546-1718
1061-4036
Publication date 2017-06-01
Sub-type Article (original research)
DOI 10.1038/ng.3861
Open Access Status Not yet assessed
Volume 49
Issue 6
Start page 825
End page 833
Total pages 9
Place of publication New York, NY, United States
Publisher Nature Publishing Group
Language eng
Abstract The contributions of coding mutations to tumorigenesis are relatively well known; however, little is known about somatic alterations in noncoding DNA. Here we describe GECCO (Genomic Enrichment Computational Clustering Operation) to analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas (PDAs) and identify commonly mutated regulatory regions. We find recurrent noncoding mutations to be enriched in PDA pathways, including axon guidance and cell adhesion, and newly identified processes, including transcription and homeobox genes. We identified mutations in protein binding sites correlating with differential expression of proximal genes and experimentally validated effects of mutations on expression. We developed an expression modulation score that quantifies the strength of gene regulation imposed by each class of regulatory elements, and found the strongest elements were most frequently mutated, suggesting a selective advantage. Our detailed single-cancer analysis of noncoding alterations identifies regulatory mutations as candidates for diagnostic and prognostic markers, and suggests new mechanisms for tumor evolution.
Q-Index Code C1
Grant ID R01 HG006677
R01 CA190092
T32 GM065094
P50 CA101955
U10 CA180944
P30 CA045508
U01 CA168409
R01 CA101973
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
Institute for Molecular Bioscience - Publications
 
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