{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,13]],"date-time":"2026-04-13T12:19:47Z","timestamp":1776082787051,"version":"3.50.1"},"reference-count":64,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T00:00:00Z","timestamp":1631923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health 5x1000 Funds-2010 program","award":["2010 program"],"award-info":[{"award-number":["2010 program"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>The MITF-E318K variant has been implicated in genetic predisposition to cutaneous melanoma. We addressed the occurrence of MITF-E318K and its association with germline status of CDKN2A and MC1R genes in a hospital-based series of 248 melanoma patients including cohorts of multiple, familial, pediatric, sporadic and melanoma associated with other tumors. Seven MITF-E318K carriers were identified, spanning every group except the pediatric patients. Three carriers showed mutated CDKN2A, five displayed MC1R variants, while the sporadic carrier revealed no variants. Germline\/tumor whole exome sequencing for this carrier revealed germline variants of unknown significance in ATM and FANCI genes and, in four BRAF-V600E metastases, somatic loss of the MITF wild-type allele, amplification of MITF-E318K and deletion of a 9p21.3 chromosomal region including CDKN2A and MTAP. In silico analysis of tumors from MITF-E318K melanoma carriers in the TCGA Pan-Cancer-Atlas dataset confirmed the association with BRAF mutation and 9p21.3 deletion revealing a common genetic pattern. MTAP was the gene deleted at homozygous level in the highest number of patients. These results support the utility of both germline and tumor genome analysis to define tumor groups providing enhanced information for clinical strategies and highlight the importance of melanoma prevention programs for MITF-E318K patients.<\/jats:p>","DOI":"10.3390\/genes12091440","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T07:52:14Z","timestamp":1632124334000},"page":"1440","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Genetic Variants and Somatic Alterations Associated with MITF-E318K Germline Mutation in Melanoma Patients"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6689-4981","authenticated-orcid":false,"given":"Elisabetta","family":"Vergani","sequence":"first","affiliation":[{"name":"Unit of Immunotherapy, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Frigerio","sequence":"additional","affiliation":[{"name":"Unit of Immunotherapy, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Dugo","sequence":"additional","affiliation":[{"name":"Platform of Integrated Biology, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0440-3221","authenticated-orcid":false,"given":"Andrea","family":"Devecchi","sequence":"additional","affiliation":[{"name":"Platform of Integrated Biology, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9899-7456","authenticated-orcid":false,"given":"Erika","family":"Feltrin","sequence":"additional","affiliation":[{"name":"CRIBI Biotechnology Center, Via Bassi 58\/B, 35131 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7066-473X","authenticated-orcid":false,"given":"Loris","family":"De Cecco","sequence":"additional","affiliation":[{"name":"Platform of Integrated Biology, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2819-0630","authenticated-orcid":false,"given":"Viviana","family":"Vallacchi","sequence":"additional","affiliation":[{"name":"Unit of Immunotherapy, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mara","family":"Cossa","sequence":"additional","affiliation":[{"name":"Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorenza","family":"Di Guardo","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siranoush","family":"Manoukian","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9233-3571","authenticated-orcid":false,"given":"Bernard","family":"Peissel","sequence":"additional","affiliation":[{"name":"Unit of Medical Genetics, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4724-0517","authenticated-orcid":false,"given":"Andrea","family":"Ferrari","sequence":"additional","affiliation":[{"name":"Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianfrancesco","family":"Gallino","sequence":"additional","affiliation":[{"name":"Melanoma and Sarcoma Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Maurichi","sequence":"additional","affiliation":[{"name":"Melanoma and Sarcoma Surgery Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Licia","family":"Rivoltini","sequence":"additional","affiliation":[{"name":"Unit of Immunotherapy, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7643-0248","authenticated-orcid":false,"given":"Marialuisa","family":"Sensi","sequence":"additional","affiliation":[{"name":"Platform of Integrated Biology, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9196-0298","authenticated-orcid":false,"given":"Monica","family":"Rodolfo","sequence":"additional","affiliation":[{"name":"Unit of Immunotherapy, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian 1, 20133 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1101\/gad.324657.119","article-title":"MITF\u2014The first 25 years","volume":"33","author":"Goding","year":"2019","journal-title":"Genes Dev."},{"key":"ref_2","first-page":"111","article-title":"The protective role of MC1R in chromosome stability and centromeric integrity in melanocytes","volume":"7","author":"Li","year":"2021","journal-title":"Cell Death 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