Concordance of hydrogen peroxide–induced 8-oxo-guanine patterns with two cancer mutation signatures of upper GI tract tumors

Abstract

Oxidative DNA damage has been linked to inflammation, cancer, and aging. Here, we have mapped two types of oxidative DNA damage, oxidized guanines produced by hydrogen peroxide and oxidized thymines created by potassium permanganate, at a single-base resolution. 8-Oxo-guanine occurs strictly dependent on the G/C sequence context and shows a pronounced peak at transcription start sites (TSSs). We determined the trinucleotide sequence pattern of guanine oxidation. This pattern shows high similarity to the cancer-associated single-base substitution signatures SBS18 and SBS36. SBS36 is found in colorectal cancers that carry mutations in MUTYH , encoding a repair enzyme that operates on 8-oxo-guanine mispairs. SBS18 is common in inflammation-associated upper gastrointestinal tract tumors including esophageal and gastric adenocarcinomas. Oxidized thymines induced by permanganate occur with a distinct dinucleotide specificity, 5′T-A/C, and are depleted at the TSS. Our data suggest that two cancer mutational signatures, SBS18 and SBS36, are caused by reactive oxygen species.

DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer

“…Elevated levels of reactive oxygen species (ROS) are observed in UVirradiated samples, consistent with 8-oxo-dG damage and mitochondrial dysfunction. Analysis of somatic mutations reveals a dose-dependent increase of C:G>A:T mutations in irradiated samples with patterns similar to the ones of COSMIC signatures SBS18/36, which were previously attributed to oxidative damage [35][36][37] . Finally, re-examination of previously generated skin cancers uncovers that SBS18/36 are ubiquitously present in melanoma and account for ~12% of the previously annotated driver mutations.…”

UVA Radiation, DNA Damage, and Melanoma

“…DNA photoproducts are major premutagenic lesions, and mapping of the photoproduct lesions genome-wide is essential to understand cellular mutational mechanisms of cancer and to define etiology of melanoma by comparing with melanoma mutational spectra. 40 , 97 (4) Furthermore, the level of DNA damage and mutations induced by UVA is expected to be lower than that of UVB-induced lesions, giving another layer of challenge to obtain UVA signatures.…”

“…(3) There is a lack of technically advanced methods to detect UVA-induced photoproducts at single-base resolution and genome-wide with high accuracy and of methodologies to reliably map the presumably rare UVA-induced mutations. DNA photoproducts are major premutagenic lesions, and mapping of the photoproduct lesions genome-wide is essential to understand cellular mutational mechanisms of cancer and to define etiology of melanoma by comparing with melanoma mutational spectra. , (4) Furthermore, the level of DNA damage and mutations induced by UVA is expected to be lower than that of UVB-induced lesions, giving another layer of challenge to obtain UVA signatures.…”

“…DNA photoproducts are major premutagenic lesions, and mapping of the photoproduct lesions genome-wide is essential to understand cellular mutational mechanisms of cancer and to define etiology of melanoma by comparing with melanoma mutational spectra. 40,97 (4) Furthermore, the level of DNA damage and mutations induced by UVA is expected to be lower than that of UVB-induced lesions, giving another layer of challenge to obtain UVA signatures. Despite of the relatively low levels of CPD formation by UVA exposure, several UVA damage studies have revealed that UVA-induced CPDs are most enriched at TT dipyrimidine sequences (TT-CPD) with around 90% of all pyrimidine dimers forming at that sequence, while UVB induces only around 50% of all CPDs as TT-CPDs.…”

Deciphering the antioxidative role of p53 against H2O2-induced DNA damage using ion mobility mass spectrometry

“…[17] Indeed, biologically relevant 8-oxo guanine patterns have been mapped in human cells treated with physiological concentrations of H2O2, resembling two mutational signatures found in cancer. [40] Monitoring the mass distribution of the DNA-p53 complexes and monomeric p53 formation over time allowed us to calculate relative abundances and propose a plausible oxidation mechanism (Figure 4D). The formation of ((Zn-p53)2Cys-OH)4DNA(p21) is followed by an oxidative dissociation where p53 dissociates from a promoter sequence for the p21 gene (Figure 4E).…”