Mahanish Jung Thapa.
Cancer is a genetic disease caused by a combination of genetic, environmental, and lifestyle factors. These factors would lead to the accumulation of multiple mutations in normal cells. Genomic analysis of cancer samples reveals that these somatic mutations form a distinct pattern on the DNA as “mutational signatures”. As of April 2023, scientists had found 78 single base substitution (SBS) signatures, 11 double base substitution (DBS) signatures, and 18 small insertions and deletions (ID) signatures from different cancer genomes, but many of these signatures still had an unknown aetiology. The current strategy to understand these unknown mutational signatures is through the characterization of mutational signatures generated from various carcinogens and mutagens in different model systems.
One of the major sources of these mutations are chemicals that belong to the “aldehyde family” and are mutagenic and carcinogenic. Formaldehyde is found mostly in cigarette smoke, automobile emissions, and many cosmetics and preservative products. Acetaldehyde is a toxic intermediate product of ethanol metabolism in humans. The International Agency for Research on Cancer (IARC) has classified formaldehyde and acetaldehyde based on their carcinogenicity in Group 1 and Group 2B, respectively, because formaldehyde is carcinogenic, and acetaldehyde is a possible cancer-causing aldehyde in humans. Endogenous formaldehyde is estimated to be 0.1 mM in human blood. Regardless of the plentiful information about the genotoxic impacts of formaldehyde and acetaldehyde, there is still minimal comprehension of their mutagenesis at the nucleotide level. The yeast mutants were isolated, and their genomes were sequenced. The yeast genomics related to formaldehyde mutagenesis showed an abundance of C > A mutations in TCn trinucleotide motifs for the SBSs (Single Base Substitutions) signature. The formaldehyde signature resembles the SBS40 signature from the Catalogue of Somatic Mutations in Cancer (COSMIC). SBS40 is a mutational signature of unknown aetiology. The SBS40 signature is the third-most common mutational signature and has been found in more than 28 cancer types. The acetaldehyde mutagenesis revealed that the acetaldehyde SBS signature has an abundance of C > T mutations in GCn trinucleotide motifs. These key findings may be helpful to understand the mutational signatures related to formaldehyde and acetaldehyde mutagenesis at the nucleotide level.
The approach that the author has used, would allow him to decipher the mutational signatures of the prevalent mutational processes as the number of cancer databases grows. Mutational signatures can be used as biomarkers to differentiate between different cancer types as prognostic indicators, therapeutic sensitivity predictors, and disease control targets. It will improve the early detection of cancer types and their prevention, and it will give important insights into aldehyde metabolism.
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Keywords: Cancer, acetaldehyde, formaldehyde, mutational signatures, SBS40
Author: Mahanish Jung Thapa, PhD candidate
Faculty of Medicine University of Ottawa, Ottawa, Canada
