Further assessment of exome-wide UVR footprints in melanoma and their possible relevance.

Abstract

C>T substitutions at dipyrimidine sites dominate the melanoma genome. We recently analyzed the exomes of spontaneous and neonatal UVR-induced murine melanomas, noting a dramatic change in the genomic footprint at C>T substitutions in the latter. Here we re-analyzed published exome-wide footprints in human melanomas stratified in terms of likely previous sun exposure. Acral and mucosal melanomas were heterogeneous in terms of base substitution types, but most C>Ts occurred in the context of 3'G, probably resulting from spontaneous deamination of the cytosine. C>Ts in sun-exposed melanomas were statistically different from acral/mucosal lesions only in preferring an adjacent 5'T and 3'C. Pyrimidine dimer adducts can form between any pyrimidine (TT, TC, CT, CC). Hence in melanoma C>Ts are overwhelmingly induced at TC or CC photoproducts, or, there are peculiarities in DNA repair that favor the mutation of cytosines with these two pyrimidines adjacent. If melanoma UVR footprints at C>Ts reflect a specific dimer type (eg, 6-4 photoproduct or cyclobutane pyrimidine dimer), these could be removed post UVR, for instance using photolyases, to potentially reduce melanoma risk. If specific modes of DNA repair and/or replication cause these footprints, methodically downregulating selected DNA polymerases in UVR-induced animal models of melanoma, combined with exome sequencing, could begin to assess this. Finally, a preponderance of TpCpC as opposed to NpCpG at C>Ts exome-wide is likely to be a good indicator of whether a melanoma has incurred even a small amount of sun damage. This information will assist epidemiological studies in predicting individual levels of sun exposure.