{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T20:55:47Z","timestamp":1764276947796,"version":"3.40.5"},"reference-count":27,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,5,3]],"date-time":"2019-05-03T00:00:00Z","timestamp":1556841600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA201757\u201001A1"],"award-info":[{"award-number":["CA201757\u201001A1"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000092","name":"U.S. National Library of Medicine","doi-asserted-by":"publisher","award":["T15\u2010LM007124\u201018"],"award-info":[{"award-number":["T15\u2010LM007124\u201018"]}],"id":[{"id":"10.13039\/100000092","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["1ULTR001067"],"award-info":[{"award-number":["1ULTR001067"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pigment Cell Melanoma Res"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Germline mutations in <jats:italic><jats:styled-content style=\"fixed-case\">CDKN<\/jats:styled-content>2A<\/jats:italic> (p16) are commonly found in patients with family history of melanoma or personal history of multiple primary melanomas. The p16 tumor suppressor gene regulates cell cycle progression and senescence through binding of cyclin\u2010dependent kinases (<jats:styled-content style=\"fixed-case\">CDK<\/jats:styled-content>) and also regulates cellular oxidative stress independently of cell cycle control. We identified a germline missense (c.350T&gt;C, p.Leu117Pro) <jats:italic><jats:styled-content style=\"fixed-case\">CDKN<\/jats:styled-content>2A<\/jats:italic> mutation in a patient who had history of four primary melanomas, numerous nevi, and self\u2010reported family history of melanoma. This particular <jats:italic><jats:styled-content style=\"fixed-case\">CDKN<\/jats:styled-content>2A<\/jats:italic> mutation has not been previously reported in prior large studies of melanoma kindreds or patients with multiple primary melanomas. Compared with wild\u2010type p16, the p16<jats:sup>L117P<\/jats:sup> mutant largely retained binding capacity for <jats:styled-content style=\"fixed-case\">CDK<\/jats:styled-content>4 and <jats:styled-content style=\"fixed-case\">CDK<\/jats:styled-content>6 but exhibited impaired capacity for repressing cell cycle progression and inducing senescence, while retaining its ability to reduce mitochondrial reactive oxygen species. Structural modeling predicted that the Leu117Pro mutation disrupts a putative adenosine monophosphate (<jats:styled-content style=\"fixed-case\">AMP<\/jats:styled-content>) binding pocket involving residue 117 in the fourth ankyrin domain. Identification of this new likely pathogenic variant extends our understanding of <jats:italic><jats:styled-content style=\"fixed-case\">CDKN<\/jats:styled-content>2A<\/jats:italic> in melanoma susceptibility and implicates <jats:styled-content style=\"fixed-case\">AMP<\/jats:styled-content> as a potential regulator of p16.<\/jats:p>","DOI":"10.1111\/pcmr.12787","type":"journal-article","created":{"date-parts":[[2019,4,19]],"date-time":"2019-04-19T05:10:00Z","timestamp":1555650600000},"page":"734-738","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A novel <i><scp>CDKN<\/scp>2A<\/i> variant (p16<sup>L117P<\/sup>) in a patient with familial and multiple primary melanomas"],"prefix":"10.1111","volume":"32","author":[{"given":"Christopher","family":"Li","sequence":"first","affiliation":[{"name":"Huntsman Cancer Institute University of Utah Health Sciences Center Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tong","family":"Liu","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute University of Utah Health Sciences Center Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Liu","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute University of Utah Health Sciences Center Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rolando","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics University of Utah Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julio C.","family":"Facelli","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics University of Utah Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1790-7023","authenticated-orcid":false,"given":"Douglas","family":"Grossman","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute University of Utah Health Sciences Center Salt Lake City Utah"},{"name":"Department of Dermatology University of Utah Health Sciences Center Salt Lake City Utah"},{"name":"Department of Oncological Sciences University of Utah Salt Lake City Utah"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,5,3]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142905.hg0720s76"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0408579102"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaad.2015.09.053"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-16-0162"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5700903"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djq363"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2006.043802"},{"key":"e_1_2_5_9_1","first-page":"6864","article-title":"CDKN2A germ\u2010line mutations in individuals with multiple cutaneous melanomas","volume":"60","author":"Hashemi J.","year":"2000","journal-title":"Cancer Research"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2017.11.019"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2012.401"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.419"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2012.085"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.10915"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-019-0732-2"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21245"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks1118"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.jid.5700689"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23258"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20084"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2014.07.003"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2010.5"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0304-419X(98)00017-1"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1038\/26155"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-437X(99)80004-5"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22225"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.19862"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt447"}],"container-title":["Pigment Cell &amp; 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