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

Published version
Peer-reviewed

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Authors

Rabbie, Roy 
Ferguson, Peter 
Couturier, Dominique-Laurent  ORCID logo  https://orcid.org/0000-0001-5774-5036
Moran, Una 

Abstract

Abstract: 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.

Description

Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440

Keywords

Brief Communication, /631/67/1922, /631/67/322, /631/67/1813/1634, /692/4028/67/1857, /692/4017/67, brief-communication

Journal Title

British Journal of Cancer

Conference Name

Journal ISSN

0007-0920
1532-1827

Volume Title

124

Publisher

Nature Publishing Group UK
Sponsorship
Department of Health | National Health and Medical Research Council (NHMRC) (APP1113867, APP1093017, APP1093017)