{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T12:41:44Z","timestamp":1773232904836,"version":"3.50.1"},"reference-count":79,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,21]],"date-time":"2023-02-21T00:00:00Z","timestamp":1676937600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RF-2016-02362288"],"award-info":[{"award-number":["RF-2016-02362288"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"name":"IRCCS Ospedale Policlinico San Martino","award":["RF-2016-02362288"],"award-info":[{"award-number":["RF-2016-02362288"]}]},{"name":"Alliance Against Cancer (ACC)","award":["RF-2016-02362288"],"award-info":[{"award-number":["RF-2016-02362288"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Although several studies have explored the molecular landscape of metastatic melanoma, the genetic determinants of therapy resistance are still largely unknown. Here, we aimed to determine the contribution of whole-exome sequencing and circulating free DNA (cfDNA) analysis in predicting response to therapy in a consecutive real-world cohort of 36 patients, undergoing fresh tissue biopsy and followed during treatment. Although the underpowered sample size limited statistical analysis, samples from non-responders had higher copy number variations and mutations in melanoma driver genes compared to responders in the BRAF V600+ subset. In the BRAF V600\u2212 subset, Tumor Mutational Burden (TMB) was twice that in responders vs. non-responders. Genomic layout revealed commonly known and novel potential intrinsic\/acquired resistance driver gene variants. Among these, RAC1, FBXW7, GNAQ mutations, and BRAF\/PTEN amplification\/deletion were present in 42% and 67% of patients, respectively. Both Loss of Heterozygosity (LOH) load and tumor ploidy were inversely associated with TMB. In immunotherapy-treated patients, samples from responders showed higher TMB and lower LOH and were more frequently diploid compared to non-responders. Secondary germline testing and cfDNA analysis proved their efficacy in finding germline predisposing variants carriers (8.3%) and following dynamic changes during treatment as a surrogate of tissue biopsy, respectively.<\/jats:p>","DOI":"10.3390\/ijms24054302","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T03:32:17Z","timestamp":1677036737000},"page":"4302","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Whole-Exome Sequencing and cfDNA Analysis Uncover Genetic Determinants of Melanoma Therapy Response in a Real-World Setting"],"prefix":"10.3390","volume":"24","author":[{"given":"Irene","family":"Vanni","sequence":"first","affiliation":[{"name":"Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-8331","authenticated-orcid":false,"given":"Lorenza","family":"Pastorino","sequence":"additional","affiliation":[{"name":"Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"},{"name":"Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Enrica Teresa","family":"Tanda","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy"},{"name":"Medical Oncology 2, 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":"Genetics of Rare Cancers, 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":"Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicola","family":"Solari","sequence":"additional","affiliation":[{"name":"Surgical Oncology, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matteo","family":"Mascherini","sequence":"additional","affiliation":[{"name":"Surgical Clinic Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesco","family":"Cabiddu","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonio","family":"Guadagno","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Unit, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5296-4325","authenticated-orcid":false,"given":"Simona","family":"Coco","sequence":"additional","affiliation":[{"name":"Lung Cancer Unit, 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 (DiMI), University of Genoa, 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":"Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"},{"name":"Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriella","family":"Pietra","sequence":"additional","affiliation":[{"name":"IRCCS Ospedale Policlinico San Martino, U.O. Immunologia, 16132 Genoa, Italy"},{"name":"Department of Experimental Medicine (DiMES), University of Genoa, 16132 Genoa, 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":"Rosaria","family":"Gangemi","sequence":"additional","affiliation":[{"name":"Bioterapie, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michele","family":"Piana","sequence":"additional","affiliation":[{"name":"Dipartimento di Matematica (MIDA), University of Genoa, 16132 Genoa, Italy"},{"name":"Life Science Computational Laboratory (LISCOMP), IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1619-1708","authenticated-orcid":false,"given":"Gabriele","family":"Zoppoli","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties (DiMI), 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":"Lorenzo","family":"Ferrando","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Medical Specialties (DiMI), 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":"Francesco","family":"Spagnolo","sequence":"additional","affiliation":[{"name":"Medical Oncology 2, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"},{"name":"Dipartimento di Scienze Chirurgiche e Diagnostiche Integrate (DISC), University of Genoa, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paola","family":"Queirolo","sequence":"additional","affiliation":[{"name":"Melanoma, Sarcoma & Rare Tumors Division, European Institute of Oncology (IEO), 20141 Milan, 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":"Genetics of Rare Cancers, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy"},{"name":"Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA A Cancer J. 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