Abstract
BackgroundData indicate that primary cutaneous melanomas are characterized by clonal heterogeneity associated with oncogenic drivers. Less data are available on the clonal changes occurring during melanoma progression. We therefore wished to analyse these changes in skin melanomas in common sites of visceral metastases as compared to the primary tumor.MethodsAn autopsy cohort of 50 patients with BRAF- and NRAS-mutant cutaneous metastatic melanomas including 139 visceral metastases was analysed for mutant allele fractions (MAF), determined by pyrosequencing and corrected for tumor/normal ratio. MAF levels were also classified as high (> 40%), medium (15–40%) or low (< 15%).ResultsContrary to NRAS mutant cases, in BRAF-mutant melanomas MAFs were found to be significantly increased in visceral metastases compared to the primary due to the significantly higher levels in lung-, adrenal gland-, intestinal- and kidney metastases. The incidence of the three MAF variants in BRAF-mutant primaries was similar, whereas the high MAF cases were found to be increased in metastases. On the other hand, medium MAF levels were more common in case of NRAS-mutant tumors. Only 31.3% of BRAF mutant- and 50% of NRAS mutant cases maintained the MAF profile of the primary in metastasis. In the majority of multiple metastatic tumors, (BRAF:71.8%, NRAS:75%) metastases were relatively homogeneous regarding MAF. However, in 6/32(18.7%) of BRAF mutant cases low MAF primaries switched to high MAF in metastases. In heterogeneous BRAF mutant metastatic cases low to high or high to low MAF conversions occurred in a further 4/32(12.5%) cases in individual metastases as compared to the primary tumors. At lower frequency, in NRAS mutant tumor such changes also observed (2/12,16.7%).ConclusionWe provided evidence for the selection of BRAF-mutant melanoma cells during metastatic progression to the lung, intestine, adrenal gland and kidney. Our findings suggest that in visceral metastases of malignant melanoma BRAF- or NRAS-MAFs are rather heterogeneous and cannot be predicted from data of the primary tumor. These data may have clinical significance when using targeted therapies.
Highlights
Data indicate that primary cutaneous melanomas are characterized by clonal heterogeneity associated with oncogenic drivers
Regarding oncogenic drivers BRAF mutation was predominant (32/50, 64%) followed by NRAS (12/50, 24%), but no KIT mutant cases were found and triple wild type cases were in minority (6/50, 12%)
Survival of metastatic melanoma patients estimated by Kaplan-Meyer analysis was not affected by the driver status of the primary tumor
Summary
Data indicate that primary cutaneous melanomas are characterized by clonal heterogeneity associated with oncogenic drivers. Detection of oncogenic mutation in the primary tumor is a routine diagnostic procedure in case of melanoma, the result of which is an important issue in treatment planning [5]. This can only be justified if the metastases represent the primary tumor accurately. One plausible explanation for these controversial results appears to be the use of molecular techniques which show different levels of sensitivity [5, 11] Another feasible explanation could be the changes in the clonal proportion of driver genes of the progressing melanoma to distant metastases [12, 13]
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