{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T05:22:55Z","timestamp":1778649775178,"version":"3.51.4"},"reference-count":56,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,10]],"date-time":"2022-12-10T00:00:00Z","timestamp":1670630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["82103055"],"award-info":[{"award-number":["82103055"]}]},{"name":"National Natural Science Foundation of China","award":["BX20200308"],"award-info":[{"award-number":["BX20200308"]}]},{"name":"National Natural Science Foundation of China","award":["212102310175"],"award-info":[{"award-number":["212102310175"]}]},{"name":"China Post-Doctoral Innovative Talent Support Program","award":["82103055"],"award-info":[{"award-number":["82103055"]}]},{"name":"China Post-Doctoral Innovative Talent Support Program","award":["BX20200308"],"award-info":[{"award-number":["BX20200308"]}]},{"name":"China Post-Doctoral Innovative Talent Support Program","award":["212102310175"],"award-info":[{"award-number":["212102310175"]}]},{"name":"Key Science and Technology Research Project of Henan Province of China","award":["82103055"],"award-info":[{"award-number":["82103055"]}]},{"name":"Key Science and Technology Research Project of Henan Province of China","award":["BX20200308"],"award-info":[{"award-number":["BX20200308"]}]},{"name":"Key Science and Technology Research Project of Henan Province of China","award":["212102310175"],"award-info":[{"award-number":["212102310175"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cutaneous melanoma (CM) is one of the most aggressive skin tumors with a poor prognosis. Ferroptosis is a newly discovered form of regulated cell death that is closely associated with cancer development and immunotherapy. The aim of this study was to establish and validate a ferroptosis-related gene (FRG) DNA methylation signature to predict the prognosis of CM patients using data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) database. A reliable four-FRG DNA methylation prognostic signature was constructed via Cox regression analysis based on TCGA database. Kaplan\u2013Meier analysis showed that patients in the high-risk group tended to have a shorter overall survival (OS) than the low-risk group in both training TCGA and validation GEO cohorts. Time-dependent receiver operating characteristic (ROC) analysis showed the areas under the curve (AUC) at 1, 3, and 5 years were 0.738, 0.730, and 0.770 in TCGA cohort and 0.773, 0.775, and 0.905 in the validation cohort, respectively. Univariate and multivariate Cox regression analyses indicated that the signature was an independent prognostic indicator of OS in patients with CM. Immunogenomic profiling showed the low-risk group of patients had a higher immunophenoscore, and most immune checkpoints were negatively associated with the risk signature. Functional enrichment analysis revealed that immune response and immune-related pathways were enriched in the low-risk group. In conclusion, we established and validated a four-FRG DNA methylation signature that independently predicts prognosis in CM patients. This signature was strongly correlated with the immune landscape, and may serve as a biomarker to guide clinicians in making more precise and personalized treatment decisions for CM patients.<\/jats:p>","DOI":"10.3390\/ijms232415677","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T01:42:27Z","timestamp":1670809347000},"page":"15677","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Identification and Validation of Ferroptosis-Related DNA Methylation Signature for Predicting the Prognosis and Guiding the Treatment in Cutaneous Melanoma"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2819-0147","authenticated-orcid":false,"given":"Wenna","family":"Guo","sequence":"first","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xue","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanna","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuting","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Zhengzhou University, Zhengzhou 450001, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0558-5728","authenticated-orcid":false,"given":"Rui","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Shanghai University, Shanghai 200444, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8334-0216","authenticated-orcid":false,"given":"Liucun","family":"Zhu","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Shanghai University, Shanghai 200444, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.1093\/annonc\/mdz411","article-title":"Cutaneous melanoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"30","author":"Michielin","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"811434","DOI":"10.3389\/fonc.2021.811434","article-title":"The Impact of Hyaluronan on Tumor Progression in Cutaneous Melanoma","volume":"11","author":"Takabe","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1056\/NEJMsb2019760","article-title":"The Rapid Rise in Cutaneous Melanoma Diagnoses","volume":"384","author":"Welch","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Siegel, R.L., Miller, K.D., Fuchs, H.E., and Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin., 2022. 72, 7\u201333.","DOI":"10.3322\/caac.21708"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1002\/cam4.1152","article-title":"Survival of cutaneous melanoma based on sex, age, and stage in the United States, 1992\u20132011","volume":"6","author":"Enninga","year":"2017","journal-title":"Cancer Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Teixido, C., Castillo, P., Martinez-Vila, C., Arance, A., and Alos, L. (2021). Molecular Markers and Targets in Melanoma. Cells, 10.","DOI":"10.3390\/cells10092320"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1007\/s40257-018-0373-6","article-title":"Unusual Clinical Presentations of Malignant Melanoma: A Review of Clinical and Histologic Features with Special Emphasis on Dermatoscopic Findings","volume":"19","author":"Cabrera","year":"2018","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1126\/science.1130481","article-title":"H2O2, a Necessary Evil for Cell Signaling","volume":"312","author":"Rhee","year":"2006","journal-title":"Science"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.molcel.2018.10.042","article-title":"Role of Mitochondria in Ferroptosis","volume":"73","author":"Gao","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1016\/j.devcel.2020.06.019","article-title":"Dietary Lipids Induce Ferroptosis in Caenorhabditiselegans and Human Cancer Cells","volume":"54","author":"Perez","year":"2020","journal-title":"Dev. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1016\/j.ijbiomac.2019.05.221","article-title":"Ferroptosis\u2014An iron- and disorder-dependent programmed cell death","volume":"135","author":"Djulbegovic","year":"2019","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12943-022-01530-y","article-title":"Ferroptosis in cancer therapy: A novel approach to reversing drug resistance","volume":"21","author":"Zhang","year":"2022","journal-title":"Mol. Cancer"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"538","DOI":"10.3389\/fcell.2020.00538","article-title":"Ferroptosis-Related Gene Signature Predicts Glioma Cell Death and Glioma Patient Progression","volume":"8","author":"Liu","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-020-19193-y","article-title":"Neutrophil-induced ferroptosis promotes tumor necrosis in glioblastoma progression","volume":"11","author":"Yee","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature14344","article-title":"Ferroptosis as a p53-mediated activity during tumour suppression","volume":"520","author":"Jiang","year":"2015","journal-title":"Nature"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1016\/j.ccell.2018.03.017","article-title":"Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress","volume":"33","author":"Tsoi","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1457","DOI":"10.1038\/s41418-017-0053-8","article-title":"miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma","volume":"25","author":"Luo","year":"2018","journal-title":"Cell Death Differ."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.it.2019.02.004","article-title":"Targeting DNA methylation and EZH2 activity to overcome melanoma resistance to immunotherapy","volume":"40","author":"Chatterjee","year":"2019","journal-title":"Trends Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1016\/j.freeradbiomed.2020.08.029","article-title":"Homocysteine induces oxidative stress and ferroptosis of nucleus pulposus via enhancing methylation of GPX4","volume":"160","author":"Zhang","year":"2020","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s13148-018-0574-0","article-title":"A five-DNA methylation signature act as a novel prognostic biomarker in patients with ovarian serous cystadenocarcinoma","volume":"10","author":"Guo","year":"2018","journal-title":"Clin. Epigenetics"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Aleotti, V., Catoni, C., Poggiana, C., Rosato, A., Facchinetti, A., and Scaini, M.C. (2021). Methylation Markers in Cutaneous Melanoma: Unravelling the Potential Utility of Their Tracking by Liquid Biopsy. Cancers, 13.","DOI":"10.3390\/cancers13246217"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13148-020-00883-9","article-title":"Prognostic and predictive value of PD-L2 DNA methylation and mRNA expression in melanoma","volume":"12","author":"Hoffmann","year":"2020","journal-title":"Clin. Epigenetics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e44310","DOI":"10.7554\/eLife.44310","article-title":"A four-DNA methylation biomarker is a superior predictor of survival of patients with cutaneous melanoma","volume":"8","author":"Guo","year":"2019","journal-title":"Elife"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.21037\/jtd.2020.03.31","article-title":"A prognostic 11-DNA methylation signature for lung squamous cell carcinoma","volume":"12","author":"Zhang","year":"2020","journal-title":"J. Thorac. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3233\/CBM-201564","article-title":"Identification of a novel CpG methylation signature to predict prognosis in lung squamous cell carcinoma","volume":"30","author":"Lee","year":"2021","journal-title":"Cancer Biomark."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1681","DOI":"10.1016\/j.cell.2015.05.044","article-title":"Genomic classification of cutaneous melanoma","volume":"161","author":"Akbani","year":"2015","journal-title":"Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/j.jaad.2021.07.011","article-title":"Molecular characterization of fast-growing melanomas","volume":"86","author":"Macagno","year":"2022","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Puglisi, R., Bellenghi, M., Pontecorvi, G., Pallante, G., Car\u00e8, A., and Mattia, G. (2021). Biomarkers for Diagnosis, Prognosis and Response to Immunotherapy in Melanoma. Cancers, 13.","DOI":"10.3390\/cancers13122875"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"856","DOI":"10.1016\/j.molmed.2021.06.014","article-title":"Ferroptosis in the tumor microenvironment: Perspectives for immunotherapy","volume":"27","author":"Xu","year":"2021","journal-title":"Trends Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/s13238-020-00789-5","article-title":"Cystine transporter SLC7A11\/xCT in cancer: Ferroptosis, nutrient dependency, and cancer therapy","volume":"12","author":"Koppula","year":"2021","journal-title":"Protein Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1016\/j.bbrc.2016.08.034","article-title":"CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation","volume":"478","author":"Yuan","year":"2016","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1158\/0008-5472.CAN-17-2476","article-title":"Pleiotropic Roles for ZEB1 in Cancer","volume":"78","author":"Caramel","year":"2018","journal-title":"Cancer Res"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/ncb3513","article-title":"The EMT-activator Zeb1 is a key factor for cell plasticity and promotes metastasis in pancreatic cancer","volume":"19","author":"Krebs","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101697","DOI":"10.1016\/j.redox.2020.101697","article-title":"Epigenetic reprogramming of epithelial-mesenchymal transition promotes ferroptosis of head and neck cancer","volume":"37","author":"Lee","year":"2020","journal-title":"Redox Biol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e003484","DOI":"10.1136\/jitc-2021-003484","article-title":"ZEB1 transcription factor promotes immune escape in melanoma","volume":"10","author":"Plaschka","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.7150\/ijbs.62393","article-title":"Genome-scale CRISPRa screening identifies MTX1 as a contributor for sorafenib resistance in hepatocellular carcinoma by augmenting autophagy","volume":"17","author":"Li","year":"2021","journal-title":"Int. J. Biol. Sci."},{"key":"ref_37","first-page":"1","article-title":"Identification of the prognostic value of ferroptosis-related gene signature in breast cancer patients","volume":"21","author":"Wang","year":"2021","journal-title":"BMC Cancer"},{"key":"ref_38","first-page":"1","article-title":"Overexpression of CISD1 Predicts Worse Survival in Hepatocarcinoma Patients","volume":"2022","author":"Lu","year":"2022","journal-title":"BioMed Res. Int."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"23282","DOI":"10.1074\/jbc.M116.749028","article-title":"The NADPH Oxidases DUOX1 and NOX2 Play Distinct Roles in Redox Regulation of Epidermal Growth Factor Receptor Signaling","volume":"291","author":"Heppner","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"17858","DOI":"10.1074\/jbc.M809761200","article-title":"ATP-mediated Activation of the NADPH Oxidase DUOX1 Mediates Airway Epithelial Responses to Bacterial Stimuli","volume":"284","author":"Boots","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e000622","DOI":"10.1136\/jitc-2020-000622","article-title":"Dual oxidase 1 limits the IFN\u03b3-associated antitumor effect of macrophages","volume":"8","author":"Meziani","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.canlet.2015.05.023","article-title":"Silencing of LRRFIP1 reverses the epithelial\u2013mesenchymal transition via inhibition of the Wnt\/\u03b2-catenin signaling pathway","volume":"365","author":"Douchi","year":"2015","journal-title":"Cancer Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1016\/j.bbrc.2014.03.105","article-title":"Higher LRRFIP1 expression in glioblastoma multiforme is associated with better response to teniposide, a type II topoisomerase inhibitor","volume":"446","author":"Li","year":"2014","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1111\/exd.14047","article-title":"DNA hypermethylation is associated with invasive phenotype of malignant melanoma","volume":"29","author":"Koroknai","year":"2020","journal-title":"Exp. Dermatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13148-017-0332-8","article-title":"Aberrant DNA methylation in melanoma: Biomarker and therapeutic opportunities","volume":"9","author":"Micevic","year":"2017","journal-title":"Clin. Epigenetics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/nature20132","article-title":"LKB1 loss links serine metabolism to DNA methylation and tumorigenesis","volume":"539","author":"Kottakis","year":"2016","journal-title":"Nature"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1097\/DAD.0000000000001856","article-title":"Value of PD-L1, PD-1, and CTLA-4 Expression in the Clinical Practice as Predictors of Response to Nivolumab and Ipilimumab in Monotherapy in Patients with Advanced Stage Melanoma","volume":"43","author":"Barrios","year":"2021","journal-title":"Am. J. Dermatopathol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1612","DOI":"10.1016\/j.cell.2020.05.017","article-title":"Intratumoral CD4+ T Cells Mediate Anti-tumor Cytotoxicity in Human Bladder Cancer","volume":"181","author":"Oh","year":"2020","journal-title":"Cell"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-019-10676-1","article-title":"IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization","volume":"10","author":"Eissmann","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1158\/0008-5472.CAN-05-4005","article-title":"Distinct Role of Macrophages in Different Tumor Microenvironments","volume":"66","author":"Lewis","year":"2006","journal-title":"Cancer Res"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1024915","DOI":"10.3389\/fonc.2022.1024915","article-title":"A ferroptosis-related gene signature associated with immune landscape and therapeutic response in osteosarcoma","volume":"12","author":"Wang","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"264","DOI":"10.2174\/0929867321666141106124315","article-title":"Targeting the NF\u03baB signaling pathways for breast cancer prevention and therapy","volume":"22","author":"Wang","year":"2015","journal-title":"Curr. Med. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"baaa021","DOI":"10.1093\/database\/baaa021","article-title":"FerrDb: A manually curated resource for regulators and markers of ferroptosis and ferroptosis-disease associations","volume":"2020","author":"Zhou","year":"2020","journal-title":"Database"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"642","DOI":"10.12968\/hmed.2019.80.11.642","article-title":"Understanding survival analysis: Actuarial life tables and the Kaplan\u2013Meier plot","volume":"80","author":"Barakat","year":"2019","journal-title":"Br. J. Hosp. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.0006-341X.2000.00337.x","article-title":"Time-Dependent ROC Curves for Censored Survival Data and a Diagnostic Marker","volume":"56","author":"Heagerty","year":"2000","journal-title":"Biometrics"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2612","DOI":"10.1038\/ncomms3612","article-title":"Inferring tumour purity and stromal and immune cell admixture from expression data","volume":"4","author":"Yoshihara","year":"2013","journal-title":"Nat. Commun."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/15677\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:37:48Z","timestamp":1760146668000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/24\/15677"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,10]]},"references-count":56,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2022,12]]}},"alternative-id":["ijms232415677"],"URL":"https:\/\/doi.org\/10.3390\/ijms232415677","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,10]]}}}