Discrepant alterations in main candidate genes among multiple primary melanomas

Abstract

BackgroundAlterations in key-regulator genes of disease pathogenesis (BRAF, cKIT, CyclinD1) have been evaluated in patients with multiple primary melanoma (MPM).MethodsOne 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.ResultsBRAF 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.ConclusionsThe 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.

Heterogeneity of BRAF, NRAS, and TERT Promoter Mutational Status in Multiple Melanomas and Association with MC1R Genotype

“…9 The overall frequency of BRAF mutations found in our sample (41.2%) was in line with two large series of melanomas 29,30 and with other Italian cohorts. 16,17,23,31 Similarly, the prevalence rate of the different BRAF V600E and BRAF V600K mutations was consistent with that previously reported. 9 Concerning clinical characteristics, our results confirm that BRAF-mutated melanomas are associated with younger age and frequently occur on the trunk.…”

“…22 To date, only two studies investigated the somatic heterogeneity of multiple melanomas within the same patient, evaluating alterations in main candidate genes by molecular methods. 23,24 However, neither of the two analyzed the possible influence of germline mutations on the somatic diversity of MPM.…”

Reduced disease‐specific survival following a diagnosis of multiple primary cutaneous malignant melanomas—a nationwide, population‐based study

“…The median tumor thickness of the index CMM in MPM‐patients in our study was thicker compared to patients with SPMs, which has previously been reported . These differences may imply a propensity among MPM‐patients to develop more aggressive disease and could reflect a clustering of fatal CMMs with specific genetic aberrations . However, more advanced T‐class in MPM‐patients could not explain the worse outcome in the present study, i.e ., the HRs were not affected after adjusting for stage and tumor thickness.…”

Association of CDK4 germline and BRAF somatic mutations in a patient with multiple primary melanomas and BRAF inhibitor resistance

“…As 45% of cutaneous malignant melanomas are found to be BRAF mutated [6], at least half the melanomas of our patient were expected to be of wild type. Previous studies, in which MPM from a single sporadic patient were analyzed for the presence of BRAF mutations, have often yielded discordant results from differing lesions [18,19]. Conversely, two recent studies have reported identical somatic mutation status in three out of four and four out of six familial MPM cases with CDK4 and CDKN2A germline mutations, respectively [8,9].…”