Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma

Michael E. Feigin, Tyler Garvin, Peter Bailey, Nicola Waddell, David K. Chang, David R. Kelley, Shimin Shuai, Steven Gallinger, John Douglas Mcpherson, Sean M. Grimmond, Ekta Khurana, Lincoln D. Stein, Andrew V. Biankin, Michael C. Schatz, David A. Tuveson

Research output: Contribution to journalArticle

26 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)825-833
Number of pages9
JournalNature Genetics
Volume49
Issue number6
DOIs
StatePublished - Jun 1 2017

ASJC Scopus subject areas

  • Genetics

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    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), 825-833. https://doi.org/10.1038/ng.3861