The Genetic Evolution of Acral Melanoma

Acral melanoma is a rare melanoma subtype arising on the sole, palm, or nail apparatus. We performed whole-exome sequencing (WES) for a cohort of 35 acral melanoma patients. For each patient, we sequenced multiple tumor areas representing different tumor stages, including the in situ and invasive portions of the primary tumor and available regional or distant metastases. Normal areas were included for all except one patient. We identified distinct evolutional trajectory compared to melanomas arising on the sun-exposed skin. Whole-genome sequencing and targeted sequencing were additionally performed for a subset of the samples. Particularly, in acral melanomas, complex genomic aberrations, characterized by clustered copy number transitions and focal amplifications, and telomerase reverse transcriptase (TERT) activating alterations occur very early during evolution, while MAP-kinase pathway mutations, such as BRAF V600E and NRAS hotspot mutations, can occur late and often result in striking intra-tumor heterogeneity. ]]>
Inclusion Criteria: Acral melanoma patients with at least two out of the three tumor progression stages (in situ, invasive and metastasis). In few instances, patients with only one stage, either invasive or metastasis, were included, but multiple invasive areas or metastases were sampled.Exclusion Criteria: Acral melanoma patients with no or only one tumor area successfully sequenced were excluded. ]]>