Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma
Web of Science
AuthorFeigin, ME; Garvin, T; Bailey, P; Waddell, N; Chang, DK; Kelley, DR; Shuai, S; Gallinger, S; McPherson, JD; Grimmond, SM; ...
Source TitleNature Genetics
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sGrimmond, Sean
AffiliationCentre for Cancer Research
Document TypeJournal Article
CitationsFeigin, M. E., Garvin, T., Bailey, P., Waddell, N., Chang, D. K., Kelley, D. R., Shuai, S., Gallinger, S., McPherson, J. D., Grimmond, S. M., Khurana, E., Stein, L. D., Biankin, A. V., Schatz, M. C. & Tuveson, D. A. (2017). Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma. NATURE GENETICS, 49 (6), pp.825-+. https://doi.org/10.1038/ng.3861.
Access StatusAccess this item via the Open Access location
Open Access URLPublished version
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.
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