Melanoma of unknown primary (MUP) is an uncommon phenomenon whereby patients 
present with metastatic disease without an evident primary site. To determine 
their likely site of origin, we combined exome sequencing from 33 MUPs to assess 
the total rate of somatic mutations and degree of UV mutagenesis. An independent 
cohort of 91 archival MUPs was also screened for 46 hot spot mutations highly 
prevalent in melanoma including BRAF, NRAS, KIT, GNAQ, and GNA11. Results showed 
that the majority of MUPs exhibited high somatic mutation rates, high ratios of 
C>T/G>A transitions, and a high rate of BRAF (45 of 101, 45%) and NRAS (32 of 
101, 32%) mutations, collectively indicating a mutation profile consistent with 
cutaneous sun-exposed melanomas. These data suggest that a significant 
proportion of MUPs arise from regressed or unrecognized primary cutaneous 
melanomas or arise de novo in lymph nodes from nevus cells that have migrated 
from the skin.