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

doi:10.3389/fgene.2021.671866

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

Front Genet. 2021 May 19:12:671866. doi: 10.3389/fgene.2021.671866. eCollection 2021.

Authors

Affiliations

¹ National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, United States.
² Center for Collaborative Research in Health Disparities - RCMI Program, University of Puerto Rico, San Juan, Puerto Rico.
³ Department of Pathology and Molecular Medicine, School of Medicine, Queen's University, Kingston, ON, Canada.
⁴ Integrated Informatics Services Core - RCMI, University of Puerto Rico, San Juan, Puerto Rico.
⁵ Department Microbiology and Molecular Genetics, University of California, Davis, Davis, CA, United States.
⁶ Life Science Research Centre, Faculty of Science, University of Ostrava, Ostrava, Czechia.
⁷ Coordinating Center for Clinical Trials, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
⁸ Martsinovsky Institute of Medical Parasitology, Tropical and Vector Borne Diseases, Sechenov First Moscow State Medical University, Moscow, Russia.
⁹ Institute of Medical Genetics, Cardiff University, Cardiff, United Kingdom.
¹⁰ Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE, United States.
¹¹ Department of Microbiology and Pathology, Biochemistry and Molecular Biology, Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, United States.
¹² Department of Genetics and Biotechnology, Saint-Petersburg State University, Saint-Petersburg, Russia.

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.

Keywords: computational biology; database; frequency matrices; gene expression; immunoglobulin genes; somatic hypermutation; tumor cells.