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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,\n                    <jats:italic>KRAS<\/jats:italic>\n                    was the most significantly enriched driver gene, with 4\/50 (8%) of brain metastases harbouring non-synonymous mutations. Hotspot\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutations were mutually exclusive from\n                    <jats:italic>BRAF<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>V600<\/jats:italic>\n                    <\/jats:sup>\n                    ,\n                    <jats:italic>NRAS<\/jats:italic>\n                    and\n                    <jats:italic>HRAS<\/jats:italic>\n                    mutations and were associated with a reduced overall survival from the resection of brain metastases (HR 10.01,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.001). Mutations in\n                    <jats:italic>KRAS<\/jats:italic>\n                    were clonal and concordant with extracranial disease, suggesting that these mutations are likely present within the primary. Our analyses suggest that\n                    <jats:italic>KRAS<\/jats:italic>\n                    mutations could help identify patients with primary melanoma at higher risk of brain metastases who may benefit from more intensive, protracted surveillance.\n                  <\/jats:p>","DOI":"10.1038\/s41416-020-01090-2","type":"journal-article","created":{"date-parts":[[2020,10,6]],"date-time":"2020-10-06T21:03:24Z","timestamp":1602018204000},"page":"156-160","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["The mutational landscape of melanoma brain metastases presenting as the first visceral site of recurrence"],"prefix":"10.1038","volume":"124","author":[{"given":"Roy","family":"Rabbie","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peter","family":"Ferguson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0984-1477","authenticated-orcid":false,"given":"Kim","family":"Wong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5774-5036","authenticated-orcid":false,"given":"Dominique-Laurent","family":"Couturier","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Una","family":"Moran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Clinton","family":"Turner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick","family":"Emanuel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kerstin","family":"Haas","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jodi M.","family":"Saunus","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Morgan R.","family":"Davidson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sunil R.","family":"Lakhani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brindha","family":"Shivalingam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Georgina V.","family":"Long","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christine","family":"Parkinson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iman","family":"Osman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8991-0013","authenticated-orcid":false,"given":"Richard A.","family":"Scolyer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4875-7021","authenticated-orcid":false,"given":"Pippa","family":"Corrie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9490-0306","authenticated-orcid":false,"given":"David J.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,10,7]]},"reference":[{"key":"1090_CR1","doi-asserted-by":"publisher","first-page":"e486","DOI":"10.1016\/S1470-2045(15)00141-2","volume":"16","author":"T Ajithkumar","year":"2015","unstructured":"Ajithkumar, T., Parkinson, C., Fife, K., Corrie, P. & Jefferies, S. Evolving treatment options for melanoma brain metastases. Lancet Oncol. 16, e486\u2013e497 (2015).","journal-title":"Lancet Oncol."},{"key":"1090_CR2","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1016\/S1470-2045(18)30139-6","volume":"19","author":"GV Long","year":"2018","unstructured":"Long, G. V., Atkinson, V., Lo, S., Sandhu, S., Guminski, A. D., Brown, M. P. et al. Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. Lancet Oncol. 19, 672\u2013681 (2018).","journal-title":"Lancet Oncol."},{"key":"1090_CR3","doi-asserted-by":"crossref","unstructured":"Haydu, L. E., Lo, S. N., McQuade, J. L., Amaria, R. N., Wargo, J., Ross, M. I. et al. Cumulative incidence and predictors of CNS metastasis for patients with American Joint Committee on Cancer 8th Edition stage III melanoma. J. Clin. 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Cancer Cell 21, 751\u2013764 (2012).","journal-title":"Cancer Cell"}],"container-title":["British Journal of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41416-020-01090-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41416-020-01090-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41416-020-01090-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,6]],"date-time":"2021-10-06T20:08:19Z","timestamp":1633550899000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41416-020-01090-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,7]]},"references-count":13,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,1,5]]}},"alternative-id":["1090"],"URL":"https:\/\/doi.org\/10.1038\/s41416-020-01090-2","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.02.17.952630","asserted-by":"object"}]},"ISSN":["0007-0920","1532-1827"],"issn-type":[{"value":"0007-0920","type":"print"},{"value":"1532-1827","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,7]]},"assertion":[{"value":"23 February 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 June 2020","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 August 2020","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 October 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All cases were ethically approved by the local Institutional Review Boards (REC approval reference numbers; HREC\/RPAH\/444, 16\/CEN\/149, 10362, 11\/NE\/0312, HREC 2005\/022 and 16\/CEN\/149 for the six participating academic centres), as well as by the Sanger Institute\u2019s human materials and data management committee. All patients provided written informed consent in accordance with the Declaration of Helsinki. All samples and clinical details are listed in Supplementary Table\u00a0\n                      \n                      .","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All the whole-exome and targeted sequencing data (including raw sequencing files, variant calls and copy number calls) have been deposited at the European Genome-Phenome Archive (\n                      \n                      at the EBI) under study accession ID EGAS00001002107.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"G.V.L. is consultant advisor to Amgen, Aduro, Array, BMS, MERCK, Novartis, Roche and Pierre-Fabre. R.A.S. has received fees for professional services from MSD, BMS, Novartis, Myriad and NeraCare. D.J.A. is a consultant for Microbiotica. All other authors report no conflicts of interest.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This work was supported by Cancer Research UK and the Wellcome Trust, NHMRC Program Funding to S.R.L. (APP1113867) and NHMRC Program Funding to R.A.S. and G.V.L. (APP1093017). R.A.S. and G.V.L. are supported by NHMRC Practitioner Fellowships. G.V.L. is supported by the University of Sydney Medical Foundation. The funders\/sponsors had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript and decision to submit the manuscript for publication.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding information"}}]}}