[Mapping DNA damage to understand somatic mutagenesis]

Somatic mutation theory explains how DNA damage can lead to the malignant transformation of cells. It therefore elucidates the connection between genotoxic agents and cancers. Mutational spectra, which tend to be characteristic of a cancer type, are available for certain genes like p53 which is frequently mutated in tumors. A mutational spectrum could therefore be the signature of the genotoxic agent(s) at the origin of the malignant transformation. Ligation-mediated PCR (LMPCR) is a genomic sequencing method that can be used for the mapping of DNA damage at nucleotide resolution. Such a mapping can then be compared to a mutational spectrum to test the hypothesis that implies one agent can cause mutations into one cancer type. LMPCR has been used this way to map DNA damage generated by different UV wavelengths. The frequently damaged sites following UVB irradiation correlate with the mutational spectrum of p53 in skin cancer. Similarly, BPDE, the activated form of the benzo[a]pyrene present in tobacco smoke, generates frequent adducts at sites corresponding to mutation hotspots of p53 in lung cancers. Still, the correlation between BPDE damage sites and p53 mutations is not perfect and this suggests a role of other genotoxic substances that are also present in tobacco smoke, such as the nitrosamine NNK. Finally, and beyond this objective of better understanding somatic mutagenesis, LMPCR is commonly used whenever DNA damage frequency and/or repair is to be investigated.