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

Julieta H Sepulveda-Yanez,Diego Alvarez-Saravia,Marcelo A Navarrete,Jacqueline Aldridge,Hendrik Veelken,Jose Fernandez-Goycoolea,Roberto Uribe-Paredes,Ward Posthuma,Cornelis A M Van Bergen

doi:10.3390/ijms222313015

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.

Highlights

The median variant allelic frequency of tumor samples was significantly higher in chronic lymphocytic leukemia (CLL)/MBL as compared to Follicular lymphoma (FL) (Figure 2B); this is preserved in the CLL mutated and unmutated groups (Supplementary Figure S3B)
We defined the mutational processes that shape the mutational landscape of FL and CLL and integrated these signatures with sub-chromosomal conformation data
In CLL, mutational signatures are evenly distributed across chromatin compartments

Summary

Introduction

That is, the uncontrolled proliferation of transformed cells, is generally attributable to acquired or inherited genetic variants that affect crucial cellular pathways [1]. Acquired mutations can be caused by environmental influences or stochastic errors in DNA replication [2,3]. Particular mutagenic mechanisms generate distinguishable mutational signatures across a cancer cell’s genome [4,5]. Somatic hypermutation (SHM) represents an endogenous mutator mechanism in B lymphocytes. SHM targets immunoglobulin genes (IG) and is dependent on the expression of activation-induced deaminase (AID) in germinal center reactions

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