DNA Methylation, Deamination, and Translesion Synthesis Combine to Generate Footprint Mutations in Cancer Driver Genes in B-Cell Derived Lymphomas and Other Cancers.

Igor B Rogozin,Lennard Y Poliakov,Anna R Panchenko,Elena Schwartz,Artem G Lada,David N Cooper,Kelvin Carrasquillo-Carrión,Vyacheslav Yurchenko,Kathrin Tyryshkin,Youri I Pavlov,Andreu Saura,Abiel Roche-Lima

doi:10.3389/fgene.2021.671866

Abstract

Cancer genomes harbor numerous genomic alterations and many cancers accumulate thousands of nucleotide sequence variations. A prominent fraction of these mutations arises as a consequence of the off-target activity of DNA/RNA editing cytosine deaminases followed by the replication/repair of edited sites by DNA polymerases (pol), as deduced from the analysis of the DNA sequence context of mutations in different tumor tissues. We have used the weight matrix (sequence profile) approach to analyze mutagenesis due to Activation Induced Deaminase (AID) and two error-prone DNA polymerases. Control experiments using shuffled weight matrices and somatic mutations in immunoglobulin genes confirmed the power of this method. Analysis of somatic mutations in various cancers suggested that AID and DNA polymerases η and θ contribute to mutagenesis in contexts that almost universally correlate with the context of mutations in A:T and G:C sites during the affinity maturation of immunoglobulin genes. Previously, we demonstrated that AID contributes to mutagenesis in (de)methylated genomic DNA in various cancers. Our current analysis of methylation data from malignant lymphomas suggests that driver genes are subject to different (de)methylation processes than non-driver genes and, in addition to AID, the activity of pols η and θ contributes to the establishment of methylation-dependent mutation profiles. This may reflect the functional importance of interplay between mutagenesis in cancer and (de)methylation processes in different groups of genes. The resulting changes in CpG methylation levels and chromatin modifications are likely to cause changes in the expression levels of driver genes that may affect cancer initiation and/or progression.

Highlights

Epigenetic reprogramming in cancer genomes creates a distinct DNA methylation landscape encompassing clustered sites of hypermethylation at regulatory regions and protein-coding genes separated by long intergenic tracks of hypomethylated regions
A prominent fraction of these mutations arises as a consequence of the off-target activity of enzymes participating in somatic hypermutation (SHM) in immunoglobulin (Ig) genes: DNA/RNA editing cytosine deaminases of the Activation Induced Deaminase (AID)/APOBEC family and the replication/repair of edited sites by DNA polymerases, as deduced by the analysis of the DNA sequence context of mutations in different cancer tissues (Alexandrov et al, 2013; Roberts and Gordenin, 2014; Swanton et al, 2015; Granadillo Rodriguez et al, 2020)
AID, DNA pol η and pol θ are involved in SHM in immunoglobulin genes (Revy et al, 2000; Matsuda et al, 2001; Pavlov et al, 2002; Zan et al, 2005; Neuberger and Rada, 2007; Arana et al, 2008; Bhattacharya et al, 2008), this role for both polymerases has been questioned (Dörner and Lipsky, 2001; Martomo et al, 2008)

Summary

Introduction

Epigenetic reprogramming in cancer genomes creates a distinct DNA methylation landscape encompassing clustered sites of hypermethylation at regulatory regions and protein-coding genes separated by long intergenic tracks of hypomethylated regions. Such changes in DNA methylation landscape are displayed by most cancer types, and have the potential to serve as a universal cancer biomarker (Sina et al, 2018; Oliver et al, 2021). Analyses of various types of cancer by means of this technique has yielded a set of 30–50 distinct mutation signatures implying many mechanisms of hypermutation in cancer cells (Alexandrov and Stratton, 2014; Goncearenco et al, 2017; Rogozin et al, 2018c; Islam and Alexandrov, 2021)

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Results

Conclusion