The Noncoding Mutational Landscape of Pancreatic Cancer Reveals Recurrent Somatic Mutations in Enhancer Regions

Area of Science:

• Genomics
• Cancer Biology
• Molecular Oncology

Background:

• The coding genome of pancreatic cancer is well-studied, but the noncoding genome remains largely unexplored.
• Understanding noncoding elements is crucial for a comprehensive view of pancreatic cancer development.

Purpose of the Study:

• To investigate the role of the noncoding genome, including promoters and enhancers, in pancreatic cancer.
• To identify specific mutational patterns and functional consequences within noncoding regions.

Main Methods:

• Whole-genome sequencing of two patient cohorts.
• Analysis of coding and noncoding regions (promoters, enhancers, noncoding-nonenhancer).
• Comparison of mutation burden and signatures between treated and untreated cancers.
• Identification and analysis of recurrent somatic mutations in conserved enhancer regions using cross-species genome comparisons.
• RNA sequencing to assess the impact of enhancer mutations on gene expression.

Main Results:

• Treated pancreatic cancers exhibit a higher mutational burden across all analyzed genomic regions.
• The relative proportion of mutations across regions remains consistent despite treatment.
• Enhancers show a lower mutation rate per megabase compared to other noncoding regions.
• Enhancers possess a distinct mutational signature, notably enriched for SBS39.
• Recurrent mutations in conserved enhancers target transcription factors crucial for pancreatic development and cancer (e.g., KLF5, TP63).
• Mutations in enhancers significantly alter gene expression, often leading to loss of expression.

Conclusions:

• Conserved enhancer regions harbor recurrent somatic mutations that represent a novel source of genetic alterations in pancreatic cancer.
• These mutations affect genes critical for pancreatic lineage, suggesting a significant role in tumorigenesis.
• The findings highlight the functional importance of noncoding elements, specifically enhancers, in pancreatic cancer biology.