Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma
No Preview Available
Associated Records
Authors
File Licence
Editors
Date
2017-06-01
Source Title
Nature Genetics
Journal Title
Journal ISSN
Volume Title
Publisher
NATURE PORTFOLIO
Melbourne Authors
Affiliation
Centre for Cancer Research
Document Type
Journal Article
Subject Code
Citation
Feigin, 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.825-833. https://doi.org/10.1038/ng.3861.
Access Status
Access this item via the Open Access location
DOI
Access URL
Open Access URL
Open Access at PMC
Linked Resource URL
NHMRC Grant Code
ARC Grant Code
Description
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.