{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T21:45:56Z","timestamp":1788299156221,"version":"build-2803163510"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T00:00:00Z","timestamp":1724198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1062935"],"award-info":[{"award-number":["APP1062935"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Centre of Research Excellence for the Study of Naevi","award":["APP1099021"],"award-info":[{"award-number":["APP1099021"]}]},{"name":"Centre of Research Excellence for the Study of Naevi","award":["APP1137127"],"award-info":[{"award-number":["APP1137127"]}]},{"name":"NHMRC Early Career Fellowship to M.S.S","award":["APP1106491"],"award-info":[{"award-number":["APP1106491"]}]},{"name":"NHMRC Early Career Fellowship to M.S.S","award":["APP1160757"],"award-info":[{"award-number":["APP1160757"]}]},{"name":"NHMRC Early Career Fellowship to M.S.S","award":["2022\/GNT2018514"],"award-info":[{"award-number":["2022\/GNT2018514"]}]},{"DOI":"10.13039\/100015539","name":"Australian Government","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015539","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008018","name":"Victorian Cancer Agency","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008018","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100015626","name":"Melanoma Institute Australia","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100015626","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Approximately 2\u201320% of cutaneous melanomas (CMs) are diagnosed as amelanotic\/hypopigmented melanoma (AHM) and represent a challenge for early diagnosis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To investigate loss-of-function mutations in key pigmentation genes in matched germline and AHM, as well as pigmented melanoma (PM), tumour DNA samples.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Analysis of clinical and histopathological characteristics \u2013 together with whole-exome sequencing data of 34 fresh frozen primary CMs, graded according to the amount of pigmentation present \u2013 was performed. Together with germline and somatic variant analysis, 30 samples had previously been analysed for copy number aberration (CNA) changes. This study focused on germline and somatic variants in the coding region of 16 genes known to be associated with albinism\/hypopigmentation or variation in human pigmentation in all samples. Chromosomal regions encompassing these 16 genes were examined for DNA copy loss or gain.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The finding that red hair-related MC1R and TYR R402Q loss-of-activity gene variant alleles and genotypes are associated with AHM was confirmed. Germline AHM-related gene variants were enriched in 70% (n = 7\/10) of patients with AHM vs. 8% (n = 2\/24) of those with PM. This surprisingly high frequency of rare germline variants in people with AHM constitutes the \u2018first hit\u2019 and confirms that those with AHM are more likely to be albinism allele carriers than individuals with PM. Next, in CNA analysis of each tumour sample, 50% (n = 4\/8) of AHM samples with a pigmentation gene variant had loss of heterozygosity (LOH) in the region containing the corresponding gene and 25% (n = 2\/8) had LOH in chromosomal regions of two AHM-related genes.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study proposes that the likely molecular mechanism for the development of amelanogenesis in AHM is carriage of an albinism\/hypopigmentation allele followed by LOH of the corresponding gene in the tumour.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bjd\/ljae336","type":"journal-article","created":{"date-parts":[[2024,8,20]],"date-time":"2024-08-20T08:48:28Z","timestamp":1724143708000},"page":"55-62","source":"Crossref","is-referenced-by-count":7,"title":["Uncovering the molecular mechanisms of amelanotic\/hypopigmented primary cutaneous melanoma"],"prefix":"10.1093","volume":"192","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1301-0294","authenticated-orcid":false,"given":"Richard A","family":"Sturm","sequence":"first","affiliation":[{"name":"Frazer Institute, The University of Queensland, Dermatology Research Centre , Brisbane, QLD ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3288-3659","authenticated-orcid":false,"given":"Darren J","family":"Smit","sequence":"additional","affiliation":[{"name":"Frazer Institute, The University of Queensland, Dermatology Research Centre , Brisbane, QLD ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7227-632X","authenticated-orcid":false,"given":"David L","family":"Duffy","sequence":"additional","affiliation":[{"name":"Frazer Institute, The University of Queensland, Dermatology Research Centre , Brisbane, QLD ,","place":["Australia"]},{"name":"QIMR Berghofer Medical Research Institute , Brisbane, QLD ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0302-5727","authenticated-orcid":false,"given":"Catriona","family":"McLean","sequence":"additional","affiliation":[{"name":"Victorian Melanoma Service, The Alfred Hospital , Melbourne, VIC ,","place":["Australia"]},{"name":"Central Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University , Melbourne, VIC ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8991-0013","authenticated-orcid":false,"given":"Richard A","family":"Scolyer","sequence":"additional","affiliation":[{"name":"Melanoma Institute Australia, The University of Sydney , Sydney, NSW ,","place":["Australia"]},{"name":"Faculty of Medicine and Health, The University of Sydney , Sydney, NSW ,","place":["Australia"]},{"name":"Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital and NSW Health Pathology , Sydney, NSW ,","place":["Australia"]},{"name":"Charles Perkins Centre, The University of Sydney , Sydney, NSW ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8908-6071","authenticated-orcid":false,"given":"Grant A","family":"McArthur","sequence":"additional","affiliation":[{"name":"Cancer Research Division, Peter MacCallum Cancer Centre , Melbourne, VIC ,","place":["Australia"]},{"name":"Sir Peter MacCallum Department of Oncology, University of Melbourne , Parkville, VIC ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1102-8506","authenticated-orcid":false,"given":"Anthony T","family":"Papenfuss","sequence":"additional","affiliation":[{"name":"Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research , Melbourne, VIC ,","place":["Australia"]},{"name":"Research Division, Peter MacCallum Cancer Centre , Melbourne, VIC ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4510-2161","authenticated-orcid":false,"given":"Mitchell S","family":"Stark","sequence":"additional","affiliation":[{"name":"Frazer Institute, The University of Queensland, Dermatology Research Centre , Brisbane, QLD ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4770-561X","authenticated-orcid":false,"given":"H Peter","family":"Soyer","sequence":"additional","affiliation":[{"name":"Frazer Institute, The University of Queensland, Dermatology Research Centre , Brisbane, QLD ,","place":["Australia"]},{"name":"Dermatology Department, Princess Alexandra Hospital , Brisbane, QLD ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9423-3435","authenticated-orcid":false,"given":"Victoria J","family":"Mar","sequence":"additional","affiliation":[{"name":"Victorian Melanoma Service, The Alfred Hospital , Melbourne, VIC ,","place":["Australia"]},{"name":"School of Public Health and Preventive Medicine, Monash University , Melbourne, VIC ,","place":["Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,8,21]]},"reference":[{"key":"2024122223514393300_ljae336-B1","doi-asserted-by":"crossref","first-page":"4589","DOI":"10.1158\/1078-0432.CCR-13-0398","article-title":"BRAF\/NRAS wild-type melanomas have a high mutation load correlating with histologic and molecular signatures of UV damage","volume":"19","author":"Mar","year":"2013","journal-title":"Clin Cancer 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