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Here, we deploy comparative genomics to identify and validate clinically relevant drivers of melanoma metastasis. To do this, we identified a set of 976 genes whose expression level was associated with a poor outcome in patients from two large melanoma cohorts. Next, we characterised the genomes and transcriptomes of mouse melanoma cell lines defined as weakly metastatic, and their highly metastatic derivatives. By comparing expression data between species, we identified lunatic fringe (<jats:italic>LFNG)<\/jats:italic>, among 28 genes whose expression level is predictive of poor prognosis and whose altered expression is associated with a prometastatic phenotype in mouse melanoma cells. CRISPR\/Cas9\u2010mediated knockout of <jats:italic>Lfng<\/jats:italic> dramatically enhanced the capability of weakly metastatic melanoma cells to metastasise <jats:italic>in\u00a0vivo,<\/jats:italic> a phenotype that could be rescued with the <jats:italic>Lfng<\/jats:italic> cDNA. Notably, genomic alterations disrupting <jats:italic>LFNG<\/jats:italic> are found exclusively in human metastatic melanomas sequenced as part of The Cancer Genome Atlas. Using comparative genomics, we show that <jats:italic>LFNG<\/jats:italic> expression plays a functional role in regulating melanoma metastasis.<\/jats:p>","DOI":"10.1002\/1878-0261.12161","type":"journal-article","created":{"date-parts":[[2017,11,29]],"date-time":"2017-11-29T18:00:01Z","timestamp":1511978401000},"page":"239-255","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Comparative genomics reveals that loss of lunatic fringe (<i>LFNG<\/i>) promotes melanoma metastasis"],"prefix":"10.1002","volume":"12","author":[{"given":"Martin","family":"Del Castillo Velasco\u2010Herrera","sequence":"first","affiliation":[{"name":"Experimental Cancer Genetics Wellcome Trust Sanger Institute Hinxton Cambridge UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louise","family":"van der Weyden","sequence":"additional","affiliation":[{"name":"Experimental Cancer Genetics Wellcome Trust Sanger Institute 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