Cis-regulatory somatic mutations and gene-expression alteration in B-cell lymphomas

Area of Science:

• Genomics
• Cancer Biology
• Bioinformatics

Background:

• Whole-genome sequencing in cancer reveals opportunities to study somatic mutations in cis-regulatory regions.
• Previous research focused on protein-coding mutations, leaving the impact of cis-regulatory mutations on gene expression under-explored.
• B-cell lymphomas provide a model for investigating cis-regulatory mutations and their effects on gene expression.

Purpose of the Study:

• To analyze somatic mutations in cis-regulatory regions of B-cell lymphomas.
• To determine the extent to which these cancers are disrupted by cis-regulatory mutations.
• To identify cis-regulatory mutations that dysregulate gene expression programs.

Main Methods:

• Analysis of somatic mutations from 84 matched tumor-normal whole genomes of B-cell lymphomas.
• Characterization of mutations overlapping transcription factor binding sites (TFBSs).
• Integration of gene expression data with mutation data using a computational approach.

Main Results:

• Mutations in cis-regulatory regions overlapping TFBSs are enriched in promoters of genes involved in apoptosis and growth/proliferation.
• Identification of cis-regulatory mutations likely to dysregulate gene expression programs.
• Demonstration that cis-regulatory mutations impact gene expression similarly to protein-coding mutations.

Conclusions:

• Genomic mutations in both coding and regulatory regions can trigger disrupted gene expression.
• Mutated regulatory elements substantially contribute to cancer pathways.
• Integrating analysis of cis-regulatory elements and gene expression enhances biological interpretation of cancer mutational landscapes.