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We use differential expression analyses of primary tumours from 204 RNA-sequenced melanomas within a large adjuvant trial, identifying a 121 metastasis-associated gene signature. This signature strongly associated with progression-free (HR\u2009=\u20091.63,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20095.24 \u00d7 10\n                    <jats:sup>\u22125<\/jats:sup>\n                    ) and overall survival (HR\u2009=\u20091.61,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20091.67 \u00d7 10\n                    <jats:sup>\u22124<\/jats:sup>\n                    ), was validated in 175 regional lymph nodes metastasis as well as two externally ascertained datasets. The machine learning classification models trained using the signature genes performed significantly better in predicting metastases than models trained with clinical covariates (\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>AUROC<\/jats:sub>\n                    = 7.03 \u00d7 10\n                    <jats:sup>\u22124<\/jats:sup>\n                    ), or published prognostic signatures (\n                    <jats:italic>p<\/jats:italic>\n                    <jats:sub>AUROC<\/jats:sub>\n                    &lt; 0.05). The signature score negatively correlated with measures of immune cell infiltration (\u03c1\u2009=\u2009\u22120.75,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20092.2 \u00d7 10\n                    <jats:sup>\u221216<\/jats:sup>\n                    ), with a higher score representing reduced lymphocyte infiltration and a higher 5-year risk of death in stage II melanoma. Our expression signature identifies melanoma patients at higher risk of metastases and warrants further evaluation in adjuvant clinical trials.\n                  <\/jats:p>","DOI":"10.1038\/s41467-021-21207-2","type":"journal-article","created":{"date-parts":[[2021,2,20]],"date-time":"2021-02-20T04:14:59Z","timestamp":1613794499000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":62,"title":["Tumour gene expression signature in primary melanoma predicts long-term outcomes"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0453-2058","authenticated-orcid":false,"given":"Manik","family":"Garg","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5774-5036","authenticated-orcid":false,"given":"Dominique-Laurent","family":"Couturier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3603-4208","authenticated-orcid":false,"given":"J\u00e9r\u00e9mie","family":"Nsengimana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4832-578X","authenticated-orcid":false,"given":"Nuno A.","family":"Fonseca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1230-7117","authenticated-orcid":false,"given":"Matthew","family":"Wongchenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibing","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Lauss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G\u00f6ran B.","family":"J\u00f6nsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Newton-Bishop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Parkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0167-1685","authenticated-orcid":false,"given":"Mark R.","family":"Middleton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8752-8785","authenticated-orcid":false,"given":"D. 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