The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence
Menée à partir de données du projet "The Cancer Genome Atlas" et à partir de données de séquençage du génome entier de 68 échantillons tissulaires de métastases cérébrales ayant pour origine un mélanome cutané dont le premier site de propagation est le cerveau, cette étude analyse les caractéristiques mutationnelles des métastases ainsi que l'association de ces caractéristiques avec la survie globale des patients
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, p = 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.
British Journal of Cancer , article en libre accès, 2020