The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence

Brain metastases are a major cause of melanoma-related mortality and morbidity. We undertook whole-exome sequencing of 50 tumours from patients undergoing surgical resection of brain metastases presenting as the first site of visceral disease spread and validated our findings in an independent dataset of 18 patients. Brain metastases had a similar driver mutational landscape to cutaneous melanomas in TCGA. However,KRASwas the most significantly enriched driver gene, with 4/50 (8%) of brain metastases harbouring non-synonymous mutations. HotspotKRASmutations were mutually exclusive fromBRAF(V600),NRASandHRASmutations and were associated with a reduced overall survival from the resection of brain metastases (HR 10.01,p = 0.001). Mutations inKRASwere clonal and concordant with extracranial disease, suggesting that these mutations are likely present within the primary. Our analyses suggest thatKRASmutations could help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive, protracted surveillance.

Automated summary

Brain metastases in melanoma patients have a similar mutational landscape to cutaneous melanomas, with KRAS being the most significantly enriched driver gene. Mutations in KRAS may help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive surveillance.