Integration of Mutational Signature Analysis with 3D Chromatin Data Unveils Differential AID-Related Mutagenesis in Indolent Lymphomas

Abstract

Activation-induced deaminase (AID) is required for somatic hypermutation in immunoglobulin genes, but also induces off-target mutations. Follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL), the most frequent types of indolent B-cell tumors, are exposed to AID activity during lymphomagenesis. We designed a workflow integrating de novo mutational signatures extraction and fitting of COSMIC (Catalogue Of Somatic Mutations In Cancer) signatures, with tridimensional chromatin conformation data (Hi-C). We applied the workflow to exome sequencing data from lymphoma samples. In 33 FL and 30 CLL samples, 42% and 34% of the contextual mutations could be traced to a known AID motif. We demonstrate that both CLL and FL share mutational processes dominated by spontaneous deamination, failures in DNA repair, and AID activity. The processes had equiproportional distribution across active and nonactive chromatin compartments in CLL. In contrast, canonical AID activity and failures in DNA repair pathways in FL were significantly higher within the active chromatin compartment. Analysis of DNA repair genes revealed a higher prevalence of base excision repair gene mutations (p = 0.02) in FL than CLL. These data indicate that AID activity drives the genetic landscapes of FL and CLL. However, the final result of AID-induced mutagenesis differs between these lymphomas depending on chromatin compartmentalization and mutations in DNA repair pathways.

Chromatin and the Cellular Response to Particle Radiation-Induced Oxidative and Clustered DNA Damage

“…Further to this, in cancers with defects in transcriptionally coupled nucleotide excision repair (TC-NER), there is a strand bias in accumulation of mutations contributing to a signature which are more commonly found in euchromatic regions ( Jager et al, 2019 ). There has been some research into combining COSMIC signatures with high-throughput chromosome conformation capture (Hi-C), which was used to assess differences in mutational processes acting in transcriptionally active vs. non-active chromatin in follicular lymphoma and chronic lymphocytic leukemia ( Sepulveda-Yanez et al, 2021 ). To the best of our knowledge, no such work has been performed for ionizing radiation exposure.…”