Further assessment of exome wide UVR signatures in melanoma

P Mukhopadhyay and GJ Walker

QIMR Berghofer Medical Research Institute

C>T substitutions at dipyrimidine sites dominate the melanoma genome. We analyzed the exomes of spontaneous and neonatal UVR-induced murine melanomas, noting a dramatic change in the genomic footprint at C>T substitutions only after a single previous exposure. It suggested a preference for particular neighbouring pyrimidines at C>T SBSs, rather than “any” pyrimidine. In order to compare our findings with human melanoma genome and to confirm the kind of pyrimidine dimers most likely to drive melanoma, we re-analyzed published exome-wide footprints in human melanomas that were stratified in terms of likely levels of sun exposure. We utilized the Wellcome Trust Sanger Institute (WTSI) mutational signature package to detect mutational signatures in a particular cohort. Acral and mucosal melanomas were heterogeneous, but most C>Ts occurred in the context of 3′G, consistent with spontaneous deamination of the cytosine. C>Ts in the sun-exposed melanomas were statistically different from acral/mucosal lesions only for 5′T and 3′C. We hypothesize that C>Ts in melanoma either are overwhelmingly induced at TC or CC photoproducts, or that there are differences in DNA repair with respect to specific pyrimidines adjacent to the mutated cytosine that result in these signatures footprints at C>Ts in melanoma. We observed that the TpCpC signature appears to differentiate melanomas that have incurred some sun exposure, from those that have incurred none.