{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T19:27:59Z","timestamp":1770578879069,"version":"3.49.0"},"reference-count":36,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T00:00:00Z","timestamp":1671148800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["RF-2016-02362288 to P.G"],"award-info":[{"award-number":["RF-2016-02362288 to P.G"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Ricerca Corrente\/5x1000 funds 2019 to IRCCS Ospedale Policlinico San Martino"],"award-info":[{"award-number":["Ricerca Corrente\/5x1000 funds 2019 to IRCCS Ospedale Policlinico San Martino"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["ACC-to PG"],"award-info":[{"award-number":["ACC-to PG"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alliance Against Cancer","award":["RF-2016-02362288 to P.G"],"award-info":[{"award-number":["RF-2016-02362288 to P.G"]}]},{"name":"Alliance Against Cancer","award":["Ricerca Corrente\/5x1000 funds 2019 to IRCCS Ospedale Policlinico San Martino"],"award-info":[{"award-number":["Ricerca Corrente\/5x1000 funds 2019 to IRCCS Ospedale Policlinico San Martino"]}]},{"name":"Alliance Against Cancer","award":["ACC-to PG"],"award-info":[{"award-number":["ACC-to PG"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>ATM germline pathogenic variants were recently found enriched in high-risk melanoma patients. However, ATM loss of heterozygosity (LOH) has never been investigated in melanoma and, therefore, a causal association with melanoma development has not been established yet. The purpose of this study was to functionally characterize 13 germline ATM variants found in high-risk melanoma patients\u2014and classified by in silico tools as pathogenic, uncertain significance, or benign\u2014using multiple assays evaluating ATM\/pATM expression and\/or LOH in melanoma tissues and cell lines. We assessed ATM status by Immunohistochemistry (IHC), Western Blot, Whole-Exome Sequencing\/Copy Number Variation analysis, and RNA sequencing, supported by Sanger sequencing and microsatellite analyses. For most variants, IHC results matched those obtained with in silico classification and LOH analysis. Two pathogenic variants (p.Ser1135_Lys1192del and p.Ser1993ArgfsTer23) showed LOH and complete loss of ATM activation in melanoma. Two variants of unknown significance (p.Asn358Ile and p.Asn796His) showed reduced expression and LOH, suggestive of a deleterious effect. This study, showing a classic two-hit scenario in a well-known tumor suppressor gene, supports the inclusion of melanoma in the ATM-related cancer spectrum.<\/jats:p>","DOI":"10.3390\/ijms232416027","type":"journal-article","created":{"date-parts":[[2022,12,16]],"date-time":"2022-12-16T04:30:00Z","timestamp":1671165000000},"page":"16027","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Ataxia-Telangiectasia Mutated Loss of Heterozygosity in Melanoma"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-8331","authenticated-orcid":false,"given":"Lorenza","family":"Pastorino","sequence":"first","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy"},{"name":"Genetica dei Tumori Rari, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1534-0521","authenticated-orcid":false,"given":"Bruna","family":"Dalmasso","sequence":"additional","affiliation":[{"name":"Genetica dei Tumori Rari, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9214-4279","authenticated-orcid":false,"given":"Eleonora","family":"Allavena","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Vanni","sequence":"additional","affiliation":[{"name":"Genetica dei Tumori Rari, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3603-2111","authenticated-orcid":false,"given":"Filippo","family":"Ugolini","sequence":"additional","affiliation":[{"name":"Section of Anatomic Pathology, Department of Health Sciences, University of Florence, 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gianna","family":"Baroni","sequence":"additional","affiliation":[{"name":"Section of Anatomic Pathology, Department of Health Sciences, University of Florence, 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4683-4951","authenticated-orcid":false,"given":"Michela","family":"Croce","sequence":"additional","affiliation":[{"name":"Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Guadagno","sequence":"additional","affiliation":[{"name":"Anatomia Patologica, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Cabiddu","sequence":"additional","affiliation":[{"name":"Anatomia Patologica, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2569-0832","authenticated-orcid":false,"given":"Virginia","family":"Andreotti","sequence":"additional","affiliation":[{"name":"Genetica dei Tumori Rari, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0337-0168","authenticated-orcid":false,"given":"William","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy"},{"name":"Genetica dei Tumori Rari, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriele","family":"Zoppoli","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy"},{"name":"Clinica di Medicina Interna a Indirizzo Oncologico, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4025-7930","authenticated-orcid":false,"given":"Lorenzo","family":"Ferrando","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy"},{"name":"Clinica di Medicina Interna a Indirizzo Oncologico, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrica Teresa","family":"Tanda","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy"},{"name":"Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Spagnolo","sequence":"additional","affiliation":[{"name":"Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8907-772X","authenticated-orcid":false,"given":"Chiara","family":"Menin","sequence":"additional","affiliation":[{"name":"Immunology and Diagnostic Molecular Oncology Unit, Veneto Institute of Oncology, IOV-IRCCS, 35128 Padua, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosaria","family":"Gangemi","sequence":"additional","affiliation":[{"name":"Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5688-5923","authenticated-orcid":false,"given":"Daniela","family":"Massi","sequence":"additional","affiliation":[{"name":"Section of Anatomic Pathology, Department of Health Sciences, University of Florence, 50134 Florence, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3651-8173","authenticated-orcid":false,"given":"Paola","family":"Ghiorzo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy"},{"name":"Genetica dei Tumori Rari, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/nrc1011","article-title":"ATM and Related Protein Kinases: Safeguarding Genome Integrity","volume":"3","author":"Shiloh","year":"2003","journal-title":"Nat. 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