Discrepant alterations in main candidate genes among multiple primary melanomas

Background:Alterations in key-regulator genes of disease pathogenesis (BRAF,cKIT,CyclinD1) have been evaluated in patients with multiple primary melanoma (MPM).Methods:One hundred twelve MPM patients (96 cases with two primary melanomas, 15 with three, and 1 with four) were included into the study. Paired synchronous/asynchronous MPM tissues (N = 229) were analyzed forBRAFmutations andcKIT/CyclynD1gene amplifications.Results:BRAFmutations were identified in 109/229 (48%) primary melanomas, whereascKITandCyclinD1amplifications were observed in 10/216 (5%) and 29/214 (14%) tumor tissues, respectively. While frequency rates of BRAF mutations were quite identical across the different MPM lesions, a significant increase of cKIT (p < 0.001) andCyclinD1(p = 0.002) amplification rates was observed between first and subsequent primary melanomas. Among the 107 patients with paired melanoma samples, 53 (49.5%) presented consistent alteration patterns between first and subsequent primary tumors. About one third (40/122; 32.8%) of subsequent melanomas presented a discrepant pattern ofBRAFmutations as compared to incident primary tumors.Conclusions:The low consistency in somatic mutation patterns among MPM lesions from same patients provides further evidence that melanomagenesis is heterogeneous and different cell types may be involved. This may have implications in clinical practice due to the difficulties in molecularly classifying patients with discrepant primary melanomas.