Journal Article

Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma

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

2017

Overview

Michael Schatz, David Tuveson and colleagues analyze somatic noncoding alterations in 308 pancreatic ductal adenocarcinomas. They find recurrent noncoding regulatory mutations that correlate with differential expression of proximal genes and find that the strongest regulatory elements are more frequently mutated, suggesting a selective advantage for mutations in these regions. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/43 / 631/114 / 631/208/212 / 692/699/67/1504/1713 / 96/106 / 96/109 / Adenocarcinoma / Adenocarcinoma - genetics / Adenocarcinoma - mortality / Agriculture / analysis / Animal Genetics and Genomics / Binding sites / Biomedicine / Cancer Research / Carcinoma, Pancreatic Ductal - genetics / Carcinoma, Pancreatic Ductal - mortality / Care and treatment / Cell adhesion / Deoxyribonucleic acid / Development and progression / Diagnostic systems / DNA / Enrichment / Evolution / Gene expression / Gene Expression Regulation, Neoplastic / Gene Function / Gene mutation / Gene regulation / Genetic aspects / Genetic code / Genomes / Genomics / Health aspects / Human Genetics / Humans / Markers / Modulation / Mutation / Pancreas / Pancreatic cancer / Pancreatic Neoplasms - genetics / Pancreatic Neoplasms - mortality / Receptor-Like Protein Tyrosine Phosphatases, Class 8 - genetics / Regulatory sequences / Sodium-Potassium-Chloride Symporters - genetics / Transcription / Tumorigenesis / Tumors