Quantification and mapping of alkylation in the human genome reveal single nucleotide resolution precursors of mutational signatures

Benzo[a]pyrene is a known carcinogen found in smoke resulting from incomplete combustion of organic materials, including cigarette. It can cause DNA damage by forming DNA adducts and promoting CG>AT mutations. However, existing strategies limit the possibility to predict the mutational outcomes in cancer, based on the genome-wide damage patterns. We, for the first time, mapped the genome-wide distribution of N2-BPDE-dG adduct at single nucleotide resolution and identified its preferred genomic regions and local sequence signatures, thereby linking genome-wide damage patterns to cancer-relevant mutations. Thus, our approach can potentially uncover the early biomarkers of exposure to carcinogenic chemicals and support prevention strategies by linking specific DNA damage distribution profiles to mutations in human cancer genomes.