Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma

Feigin, M. E. et al. (2017) Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma. Nature Genetics, 49(6), pp. 825-833. (doi: 10.1038/ng.3861) (PMID:28481342) (PMCID:PMC5659388)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bailey, Dr Peter and Biankin, Professor Andrew and Grimmond, Professor Sean and Chang, Professor David
• Authors: 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., and Tuveson, D. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Genetics
• Publisher: Nature Publishing Group
• ISSN: 1061-4036
• ISSN (Online): 1546-1718
• Published Online: 08 May 2017
• Copyright Holders: Copyright © 2017 Nature America, Inc., part of Springer Nature
• First Published: First published in Nature Genetics 49(6):825-833
• Publisher Policy: Reproduced in accordance with the publisher copyright policy