{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T00:02:40Z","timestamp":1791849760071,"version":"4.3.4"},"reference-count":35,"publisher":"American Medical Association (AMA)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Dermatol"],"published-print":{"date-parts":[[2024,9,1]]},"abstract":"<jats:sec id=\"ab-doi240028-4\"><jats:title>Importance<\/jats:title><jats:p>It is unknown whether germline genetic factors influence in situ melanoma risk differently than invasive melanoma risk.<\/jats:p><\/jats:sec><jats:sec id=\"ab-doi240028-5\"><jats:title>Objective<\/jats:title><jats:p>To determine whether differences in risk of in situ melanoma and invasive melanoma are heritable.<\/jats:p><\/jats:sec><jats:sec id=\"ab-doi240028-6\"><jats:title>Design, Setting, and Participants<\/jats:title><jats:p>Three genome-wide association study meta-analyses were conducted of in situ melanoma vs controls, invasive melanoma vs controls, and in situ vs invasive melanoma (case-case) using 4 population-based genetic cohorts: the UK Biobank, the FinnGen cohort, the QSkin Sun and Health Study, and the Queensland Study of Melanoma: Environmental and Genetic Associations (Q-MEGA). Melanoma status was determined using <jats:italic>International Statistical Classification of Diseases and Related Health Problems<\/jats:italic> codes from cancer registry data. Data were collected from 1987 to 2022, and data were analyzed from September 2022 to June 2023.<\/jats:p><\/jats:sec><jats:sec id=\"ab-doi240028-7\"><jats:title>Exposure<\/jats:title><jats:p>In situ and invasive cutaneous melanoma.<\/jats:p><\/jats:sec><jats:sec id=\"ab-doi240028-8\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>To test whether in situ and invasive melanoma have independent heritable components, genetic effect estimates were calculated for single-nucleotide variants (SNV; formerly single-nucleotide polymorphisms) throughout the genome for each melanoma. Then, SNV-based heritability was estimated, the genetic correlation between melanoma subtypes was assessed, and polygenic risk scores (PRS) were generated for in situ vs invasive status in Q-MEGA participants.<\/jats:p><\/jats:sec><jats:sec id=\"ab-doi240028-9\"><jats:title>Results<\/jats:title><jats:p>A total of 6 genome-wide significant loci associated with in situ melanoma and 18 loci with invasive melanoma were identified. A strong genetic correlation (genetic <jats:italic>r<\/jats:italic>\u2009=\u20090.96; 95% CI, 0.76-1.15) was observed between the 2 classifications. Notably, loci near <jats:italic>IRF4<\/jats:italic>,<jats:italic> KLF4<\/jats:italic>, and <jats:italic>HULC<\/jats:italic> had significantly larger effects for in situ melanoma compared with invasive melanoma, while <jats:italic>MC1R<\/jats:italic> had a significantly larger effect on invasive melanoma compared with in situ melanoma. Heritability estimates were consistent for both, with in situ melanoma heritability of 6.7% (95% CI, 4.1-9.3) and invasive melanoma heritability of 4.9% (95% CI, 2.8-7.2). Finally, a PRS, derived from comparing invasive melanoma with in situ melanoma genetic risk, was on average significantly higher in participants with invasive melanoma (odds ratio per 1-SD increase in PRS, 1.43; 95% CI, 1.16-1.77).<\/jats:p><\/jats:sec><jats:sec id=\"ab-doi240028-10\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>There is much shared genetic architecture between in situ melanoma and invasive melanoma. Despite indistinguishable heritability estimates between the melanoma classifications, PRS suggest germline genetics may influence whether a person gets in situ melanoma or invasive melanoma. PRS could potentially help stratify populations based on invasive melanoma risk, informing future screening programs without exacerbating the current burden of melanoma overdiagnosis.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamadermatol.2024.2601","type":"journal-article","created":{"date-parts":[[2024,8,14]],"date-time":"2024-08-14T15:01:17Z","timestamp":1723647677000},"page":"964","source":"Crossref","is-referenced-by-count":11,"title":["Exploring the Germline Genetics of In Situ and Invasive Cutaneous Melanoma"],"prefix":"10.1001","volume":"160","author":[{"given":"Nathan","family":"Ingold","sequence":"first","affiliation":[{"name":"Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia"},{"name":"School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia"},{"name":"Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, 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Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas G.","family":"Martin","sequence":"additional","affiliation":[{"name":"Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L.","family":"Duffy","sequence":"additional","affiliation":[{"name":"Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiarash","family":"Khosrotehrani","sequence":"additional","affiliation":[{"name":"The University of Queensland, Frazer Institute, Experimental Dermatology Group, Dermatology Research Centre, Woolloongabba, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Hayward","sequence":"additional","affiliation":[{"name":"Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, 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