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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, KRAS was the most significantly enriched driver gene, with 4/50 (8%) of brain metastases harbouring non-synonymous mutations. Hotspot KRAS mutations were mutually exclusive from BRAFV600, NRAS and HRAS mutations and were associated with a reduced overall survival from the resection of brain metastases (HR 10.01, pā€‰=ā€‰0.001). Mutations in KRAS were clonal and concordant with extracranial disease, suggesting that these mutations are likely present within the primary. Our analyses suggest that KRAS mutations could help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive, protracted surveillance.


Roy Rabbie, Peter Ferguson, Kim Wong, Dominique-Laurent Couturier, Una Moran, Clinton Turner, Patrick Emanuel, Kerstin Haas, Jodi M Saunus, Morgan R Davidson, Sunil R Lakhani, Brindha Shivalingam, Georgina V Long, Christine Parkinson, Iman Osman, Richard A Scolyer, Pippa Corrie, David J Adams. The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence. British journal of cancer. 2021 Jan;124(1):156-160

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PMID: 33024263

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