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The Dutch Early-Stage Melanoma (D-ESMEL) study introduces a robust, population-based methodology to develop an absolute risk prediction model for stage I\/II melanoma, incorporating clinical, imaging, and multi-omics data to identify patients at increased risk for distant metastases. Utilizing the Netherlands Cancer Registry and Dutch Nationwide Pathology Databank, we collected primary tumor samples from early-stage melanoma patients, with and without distant metastases during follow-up. Our study design includes a discovery set of metastatic cases and matched controls to identify novel prognostic factors, followed by a validation cohort using a nested case\u2013control design to validate these factors and to build a risk prediction model. Tissue sections underwent Hematoxylin &amp; Eosin (H&amp;E) staining, RNA sequencing (RNAseq), DNA sequencing (DNAseq), immunohistochemistry (IHC), and multiplex immunofluorescence (MxIF).The discovery set included 442 primary melanoma samples (221 case\u2013control sets), with 46% stage I and 54% stage II melanomas. The median time to distant metastasis was 3.4\u00a0years, while controls had a median follow-up time of 9.8\u00a0years. The validation cohort included 154 cases and 154 controls from a random population-based selection of 5,815 patients. Our approach enabled the collection of a large number of early-stage melanoma samples from population-based databases with extensive follow-up and a sufficient number of metastatic events. This methodology in prognostic cancer research holds the potential to impact clinical decision-making through absolute risk prediction.<\/jats:p>","DOI":"10.1007\/s10654-024-01188-4","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T14:13:23Z","timestamp":1736432003000},"page":"27-42","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The Dutch Early-Stage Melanoma (D-ESMEL) study: a discovery set and validation cohort to predict the absolute risk of distant metastases in stage I\/II cutaneous melanoma"],"prefix":"10.1007","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-7157-6341","authenticated-orcid":false,"given":"Catherine","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antien L.","family":"Mooyaart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thamila","family":"Kerkour","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marieke W. 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