Identification of recurrent noncoding mutations in B-cell lymphoma using capture Hi-C

Area of Science:

• Genomics
• Cancer Biology
• Oncogenesis

Background:

• Driver mutations are key to understanding cancer development.
• Previous research on B-cell lymphoma primarily focused on the coding genome.
• The noncoding genome's role in oncogenesis remains largely unexplored.

Purpose of the Study:

• To investigate the noncoding genome for driver mutations in B-cell lymphoma.
• To identify regulatory elements and their associated mutations impacting gene expression.
• To understand the common pathways targeted by both coding and noncoding mutations.

Main Methods:

• Whole-genome sequencing of 117 B-cell lymphoma patients.
• Promoter capture Hi-C in naive B cells to define cis-regulatory elements.
• Analysis of copy number variations and single nucleotide variants in regulatory regions.

Main Results:

• Identified cis-regulatory elements with mutations significantly altering gene expression.
• Discovered copy number variations targeting CD69, IGLL5, and MMP14.
• Found single nucleotide variants in a cis-regulatory element for TPRG1.
• Demonstrated MMP14's role in Notch signaling, linking noncoding mutations to lymphomagenesis and patient survival.

Conclusions:

• The noncoding genome harbors driver mutations crucial for B-cell lymphoma.
• Chromosome conformation capture is valuable for deciphering noncoding mutations in cancer.
• This research deepens the understanding of lymphomagenesis and identifies potential therapeutic avenues.