The molecular evolution of melanoma distant metastases.

The evolution of primary melanoma to lymph node and distant metastasis is incompletely understood. We examined the genomic diversity in melanoma progression in matched primary melanomas, lymph node and distant metastases from 17 patients. Fluorescence in situ hybridization (FISH) analysis revealed cancer cell fractions with monotonic copy number alterations (CNAs), including PHIP gain and PTEN loss, in the metastatic cascade. By contrast, the cancer cell fraction with CNAs for BPTF and MITF was reduced in lymph node metastases but increased in distant metastases. Separately, the cancer cell fraction with NCOA3 CNA was comparable in primary tumors and lymph nodes yet increased in distant metastases. These results suggest enrichment of the PI3K and MITF pathways in the transition through the metastatic cascade. By contrast, next-generation sequencing analysis did not identify a consistent pattern of changes in variant allele frequency (VAF) while revealing several intriguing findings, including decreased VAF in distant metastases and distinct drivers in lymph node versus distant metastases. These results provide evidence that distant melanoma metastasis does not always emanate from lymph node metastasis. These results enhance our understanding of clonal patterns of melanoma metastasis, with possible implications for targeted therapy and metastasis competency.