{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T15:42:12Z","timestamp":1789746132784,"version":"4.0.1"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"17","license":[{"start":{"date-parts":[[2020,7,27]],"date-time":"2020-07-27T00:00:00Z","timestamp":1595808000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011713","name":"Worldwide Cancer Research","doi-asserted-by":"publisher","award":["16-0101"],"award-info":[{"award-number":["16-0101"]}],"id":[{"id":"10.13039\/100011713","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UK Biobank Resource","award":["25331"],"award-info":[{"award-number":["25331"]}]},{"name":"Australian National Health and Medical Research Council"},{"DOI":"10.13039\/501100000923","name":"Australian Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000923","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Highland Island Enterprise","award":["HMS 9353763"],"award-info":[{"award-number":["HMS 9353763"]}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["c588\/a19167"],"award-info":[{"award-number":["c588\/a19167"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["ca083115"],"award-info":[{"award-number":["ca083115"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,10,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cancers, including cutaneous melanoma, can cluster in families. In addition to environmental etiological factors such as ultraviolet radiation, cutaneous melanoma has a strong genetic component. Genetic risks for cutaneous melanoma range from rare, high-penetrance mutations to common, low-penetrance variants. Known high-penetrance mutations account for only about half of all densely affected cutaneous melanoma families, and the causes of familial clustering in the remainder are unknown. We hypothesize that some clustering is due to the cumulative effect of a large number of variants of individually small effect. Common, low-penetrance genetic risk variants can be combined into polygenic risk scores. We used a polygenic risk score for cutaneous melanoma to compare families without known high-penetrance mutations with unrelated melanoma cases and melanoma-free controls. Family members had significantly higher mean polygenic load for cutaneous melanoma than unrelated cases or melanoma-free healthy controls (Bonferroni-corrected t-test P\u2009=\u20091.5\u2009\u00d7\u200910\u22125 and 6.3\u2009\u00d7\u200910\u221245, respectively). Whole genome sequencing of germline DNA from 51 members of 21 families with low polygenic risk for melanoma identified a CDKN2A p.G101W mutation in a single family but no other candidate high-penetrance melanoma susceptibility genes. This work provides further evidence that melanoma, like many other common complex disorders, can arise from the joint action of multiple predisposing factors, including rare high-penetrance mutations, as well as via a combination of large numbers of alleles of small effect.<\/jats:p>","DOI":"10.1093\/hmg\/ddaa156","type":"journal-article","created":{"date-parts":[[2020,7,22]],"date-time":"2020-07-22T19:19:10Z","timestamp":1595445550000},"page":"2976-2985","source":"Crossref","is-referenced-by-count":12,"title":["Multiplex melanoma families are enriched for polygenic risk"],"prefix":"10.1093","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4303-8821","authenticated-orcid":false,"given":"Matthew H","family":"Law","sequence":"first","affiliation":[{"name":"Statistical Genetics, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1448-3923","authenticated-orcid":false,"given":"Lauren G","family":"Aoude","sequence":"additional","affiliation":[{"name":"Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia"},{"name":"Surgical Oncology Group, The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD 4102, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David L","family":"Duffy","sequence":"additional","affiliation":[{"name":"Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina V","family":"Long","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney, Sydney, NSW 2065, Australia"},{"name":"Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia"},{"name":"Department of Medical Oncology, Mater Hospital, North Sydney, NSW 2060, Australia"},{"name":"Department of Medical Oncology, Royal North Shore Hospital, St Leonards, NSW 2065, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7015-5452","authenticated-orcid":false,"given":"Peter A","family":"Johansson","sequence":"additional","affiliation":[{"name":"Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5336-0454","authenticated-orcid":false,"given":"Antonia L","family":"Pritchard","sequence":"additional","affiliation":[{"name":"Oncogenomics, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia"},{"name":"Genetics and Immunology, University of the Highlands and Islands, Inverness IV2 5NA, 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