Clinical, Environmental And Histological Distribution Of Braf, Nras And Tert Promoter Mutations Among Patients With Cutaneous Melanoma: A Retrospective Study Of 563 Patients

Background The distinct somatic mutations that define clinical and histopathological heterogeneity in cutaneous melanoma could be dependent on host susceptibility to exogenous factors like ultraviolet radiation. Objectives Firstly, to characterize patients with cutaneous melanoma clinically and pathologically based on the mutational status ofBRAF,NRASandTERTpromoter. Secondly, to elucidate the modified features due to the presence ofTERTpromoter mutations over the background of eitherBRAForNRASmutations. Methods We performed a retrospective study on 563 patients with melanoma by investigating somatic mutations inBRAF,NRASandTERTpromoter. Results We observed co-occurrence ofTERTpromoter mutations withBRAFandNRASmutations in 26.3% and 6.9% of melanomas, respectively. Multivariate analysis showed an independent association betweenBRAFmutations and a decreased presence of cutaneous lentigines at the melanoma site, and an increased association with the presence of anyMC1Rpolymorphism. We also observed an independent association betweenTERTpromoter mutations and increased tumour mitotic rate. Co-occurrence ofBRAFandTERTpromoter mutations was independently associated with occurrence of primary tumours at usually sun-exposed sites, lack of histological chronic sun damage in surrounding unaffected skin at the melanoma site, and increased tumour mitotic rate. Co-occurrence ofNRASandTERTpromoter mutations was independently associated with increased tumour mitotic rate. The presence ofTERTpromoter together withBRAForNRASmutations was associated with statistically significantly worse survival. Conclusions The presence ofTERTpromoter mutations discriminatesBRAF- andNRAS-mutated tumours and indicates a higher involvement of ultraviolet-induced damage and tumours with worse melanoma-specific survival than those without any mutation. These observations refine classification of patients with melanoma based on mutational status.