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. (June 2017) Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma. Nat Genet, 49 (6). pp. 825-833. ISSN 1061-4036
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 Cancer Center Program > Signal Transduction CSHL Post Doctoral Fellows CSHL labs > Schatz lab CSHL labs > Tuveson lab School of Biological Sciences > Publications CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program |
| Depositing User: | Matt Covey |
| Date: | June 2017 |
| Date Deposited: | 11 May 2017 15:18 |
| Last Modified: | 06 Jul 2021 19:21 |
| PMCID: | PMC5659388 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/34738 |
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