Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma

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. Nat Genet, 49 (6). pp. 825-833. ISSN 1061-4036

URL: https://www.ncbi.nlm.nih.gov/pubmed/28481342
DOI: 10.1038/ng.3861

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: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > mutations
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > non-coding RNA
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Schatz lab
CSHL labs > Tuveson lab
Watson School > Publications
CSHL Post Doctoral Fellows
Depositing User: Matt Covey
Date Deposited: 11 May 2017 15:18
Last Modified: 21 Jun 2017 19:33
Related URLs:
URI: http://repository.cshl.edu/id/eprint/34738

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