Discrepant alterations in main candidate genes among multiple primary melanomas

Abstract
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 for BRAF
mutations and cKIT/CyclynD1 gene amplifications.
Results: BRAF mutations were identified in 109/229 (48%) primary melanomas, whereas cKIT and CyclinD1
amplifications 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) and
CyclinD1 (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 of BRAF mutations 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.