Recurrent noncoding regulatory mutations in pancreatic ductal adenocarcinoma

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 are enriched in PDA pathways, including axon guidance and cell adhesion, and novel processes including transcription and homeobox genes. We identify mutations in protein binding sites correlating with differential expression of proximal genes and experimentally validate 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 find the strongest elements are 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 novel mechanisms for tumor evolution.