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 D McPherson, Sean M Grimmond, Ekta Khurana, Lincoln D Stein, Andrew V Biankin, Michael C Schatz, David A Tuveson

Journal: Nature genetics 2017;49(6):825-833

PMID: 28481342

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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.

Address: Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.; Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York, USA.; Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, USA.; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, UK.; QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.; The Kinghorn Cancer Centre, Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia.; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales, Australia.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, USA.; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.; Division of General Surgery, Toronto General Hospital, Toronto, Ontario, Canada.; Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.; Sandra and Edward Meyer Cancer Center, Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Medical College of Cornell University, New York, New York, USA.; Informatics and Biocomputing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland, UK.; Department of Computer Science, Johns Hopkins University, Baltimore, Maryland, USA.; Department of Biology, Johns Hopkins University, Baltimore, Maryland, USA.; Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

DOI: 10.1038/ng.3861