Combining molecular and immunohistochemical analyses of key drivers in primary melanomas: interplay between germline and somatic variations.

Due to the high mutational somatic burden of Cutaneous Malignant Melanoma (CMM) a thorough profiling of the driver mutations and their interplay is necessary to explain the timing of tumorigenesis or for the identification of actionable genetic events. The aim of this study was to establish the mutation rate of some of the key drivers in melanoma tumorigenesis combining molecular analyses and/or immunohistochemistry in 93 primary CMMs from an Italian cohort also characterized for germline status, and to investigate an interplay between germline and somatic variants. mutations were present in 68% of cases, while germline mutations were found in 16 % and p16 loss in tissue was found in 63%. promoter somatic mutations were detected in 38% of cases while the -245T>C polymorphism was found in 51% of cases. mutations were found in 39% of negative or undetermined cases. NF1 was expressed in all cases analysed. MC1R variations were both considered as a dichotomous variable or scored. While a positive, although not significant association between germline mutations, but not variants, and somatic mutation was found, we did not observe other associations between germline and somatic events. A yet undescribed inverse correlation between -245T>C polymorphism and the presence of mutation was found. It is possible to hypothesize that -245T>C polymorphism could be included in those genotypes which may influence the occurrence of BRAF mutations. Further studies are needed to investigate the role of -245T>C polymorphism as a germline predictor of somatic mutation status.