{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T04:40:24Z","timestamp":1773290424223,"version":"3.50.1"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T00:00:00Z","timestamp":1661817600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Skin cutaneous melanoma (SKCM) is a common malignancy that is associated with increased morbidity and mortality. Complement C1Q is composed of C1QA, C1QB, and C1QC and is involved in the occurrence and development of many malignant tumours. However, the effect of C1QA, C1QB, and C1QC expression on tumour immunity and prognosis of cutaneous melanoma remains unclear.<\/jats:p><jats:p><jats:bold>Methods:<\/jats:bold> First, we analysed C1QA, C1QB, and C1QC expression levels and prognostic values using Gene Expression Profiling Interactive Analysis (GEPIA) and Tumour Immune Estimation Resource (TIMER) analysis, and further validation was performed using RT-qPCR, The Human Protein Atlas, The Cancer Genome Atlas (TCGA) dataset, and Gene Expression Omnibus dataset. We then performed univariate\/multivariate Cox proportional hazard model, clinicopathological correlation, and receiver operating characteristic curve analysis using TCGA dataset and established a nomogram model. Differentially expressed genes associated with C1QA, C1QB, and C1QC in SKCM were identified and analysed using LinkedOmics, TIMER, the Search Tool for the Retrieval of Interacting Genes database, and Metascape and Cytoscape software platforms. We used TIMER, GEPIA, and single-sample gene set enrichment analysis (ssGSEA) to analyse the relationship between the three genes and the level of immune cell infiltration, biomarkers, and checkpoint expression in SKCM. Finally, GSEA was utilized to study the functional pathways of C1QA, C1QB, and C1QC enrichment in SKCM.<\/jats:p><jats:p><jats:bold>Results:<\/jats:bold> The overexpression of C1QA, C1QB, and C1QC provided significant value in the diagnosis of SKCM and has been associated with better overall survival (OS). Multivariate Cox regression analysis indicated that C1QA, C1QB, and C1QC are independent prognostic biomarkers for patients with SKCM. Immune cell infiltration, biomarkers, and checkpoints were positively correlated with the expression of C1QA, C1QB, and C1QC. Furthermore, the results of functional and pathway enrichment analysis showed that immune-related and apoptotic pathways were significantly enriched in the high-expression group of C1QA, C1QB, and C1QC.<\/jats:p><jats:p><jats:bold>Conclusion:<\/jats:bold> We found that C1QA, C1QB, and C1QC can be used as biomarkers for the diagnosis and prognosis of SKCM patients. The upregulated expression levels of these three complement components benefit patients from OS and may increase the effect of immunotherapy. This result may be due to the dual effects of anti-tumour immunity and apoptosis.<\/jats:p>","DOI":"10.3389\/fgene.2022.940306","type":"journal-article","created":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T09:24:10Z","timestamp":1661851450000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":25,"title":["Prognostic and immune-related value of complement C1Q (C1QA, C1QB, and C1QC) in skin cutaneous melanoma"],"prefix":"10.3389","volume":"13","author":[{"given":"Huanglong","family":"Yang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dehui","family":"Che","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxiang","family":"Gu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongsheng","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,8,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.3389\/fimmu.2017.01559","article-title":"Complement protein C1q binds to hyaluronic acid in the malignant pleural mesothelioma microenvironment and promotes tumor growth","volume":"8","author":"Agostinis","year":"2017","journal-title":"Front. Immunol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"e1253653","DOI":"10.1080\/2162402X.2016.1253653","article-title":"The non-inflammatory role of C1q during Her2\/neu-driven mammary carcinogenesis","volume":"5","author":"Bandini","year":"2016","journal-title":"Oncoimmunology"},{"key":"B3","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1007\/978-3-319-22539-5_2","article-title":"Melanoma epidemiology and prevention","volume":"167","author":"Berwick","year":"2016","journal-title":"Cancer Treat. Res."},{"key":"B4","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1016\/j.immuni.2013.10.003","article-title":"Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer","volume":"39","author":"Bindea","year":"2013","journal-title":"Immunity"},{"key":"B5","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1016\/s0001-7310(09)73167-9","article-title":"Malignant melanoma-a genetic overview","volume":"100","author":"Bloethner","year":"2009","journal-title":"Actas Sifiliogr."},{"key":"B6","doi-asserted-by":"publisher","first-page":"3","DOI":"10.3390\/cancers14010003","article-title":"Shared gene expression and immune pathway changes associated with progression from nevi to melanoma","volume":"14","author":"Borden","year":"2021","journal-title":"Cancers"},{"key":"B7","doi-asserted-by":"publisher","first-page":"10346","DOI":"10.1038\/ncomms10346","article-title":"C1q acts in the tumour microenvironment as a cancer-promoting factor independently of complement activation","volume":"7","author":"Bulla","year":"2016","journal-title":"Nat. Commun."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1915","DOI":"10.1016\/S0140-6736(19)32591-7","article-title":"Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study","volume":"394","author":"Burtness","year":"2019","journal-title":"Lancet"},{"key":"B9","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.jdermsci.2015.08.003","article-title":"Telomere length and the risk of cutaneous melanoma and non-melanoma skin cancer: A review of the literature and meta-analysis","volume":"80","author":"Caini","year":"2015","journal-title":"J. Dermatol. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1186\/s40425-018-0349-3","article-title":"Current landscape and future of dual anti-CTLA4 and PD-1\/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC)","volume":"6","author":"Chae","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"B11","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1093\/bmb\/ldu019","article-title":"Management of melanoma","volume":"111","author":"Corrie","year":"2014","journal-title":"Br. Med. Bull."},{"key":"B12","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1016\/j.jaad.2019.01.081","article-title":"Early detection of acral melanoma: A review of clinical, dermoscopic, histopathologic, and molecular characteristics","volume":"81","author":"Darmawan","year":"2019","journal-title":"J. Am. Acad. Dermatol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"4102","DOI":"10.1200\/JCO.2016.67.2477","article-title":"Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma","volume":"34","author":"Daud","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"4006","DOI":"10.4049\/jimmunol.0903009","article-title":"B cells are required for optimal CD4+ and CD8+ T cell tumor immunity: therapeutic B cell depletion enhances B16 melanoma growth in mice","volume":"184","author":"DiLillo","year":"2010","journal-title":"J. Immunol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1053\/j.semdp.2016.04.003","article-title":"Mucosal melanomas: Site-specific information, comparisons with cutaneous tumors, and differential diagnosis","volume":"33","author":"Dominiak","year":"2016","journal-title":"Semin. Diagn. Pathol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3389\/fimmu.2018.00014","article-title":"Recent advances in targeting CD8 T-cell immunity for more effective cancer immunotherapy","volume":"9","author":"Durgeau","year":"2018","journal-title":"Front. Immunol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1200\/EDBK_201131","article-title":"Combination immunotherapy development in melanoma","volume":"38","author":"Eggermont","year":"2018","journal-title":"Am. Soc. Clin. Oncol. Educ. Book."},{"key":"B18","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.molimm.2019.10.008","article-title":"Recombinant C1q variants modulate macrophage responses but do not activate the classical complement pathway","volume":"117","author":"Espericueta","year":"2020","journal-title":"Mol. Immunol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1593806","DOI":"10.1080\/2162402X.2019.1593806","article-title":"Prognostic value of tumor-infiltrating lymphocytes in melanoma: A systematic review and meta-analysis","volume":"8","author":"Fu","year":"2019","journal-title":"Oncoimmunology"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.3892\/or.2016.4947","article-title":"Enhancing the treatment effect on melanoma by heat shock protein 70-peptide complexes purified from human melanoma cell lines","volume":"36","author":"Gao","year":"2016","journal-title":"Oncol. Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"e19330","DOI":"10.1371\/journal.pone.0019330","article-title":"Monitoring the systemic human memory B cell compartment of melanoma patients for anti-tumor IgG antibodies","volume":"6","author":"Gilbert","year":"2011","journal-title":"PLoS One"},{"key":"B22","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1056\/NEJMoa1305133","article-title":"Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma","volume":"369","author":"Hamid","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1471-2105-14-7","article-title":"Gsva: Gene set variation analysis for microarray and RNA-seq data","volume":"14","author":"Hanzelmann","year":"2013","journal-title":"BMC Bioinforma."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e5755","DOI":"10.1371\/journal.pone.0005755","article-title":"Complement C1q activates tumor suppressor WWOX to induce apoptosis in prostate cancer cells","volume":"4","author":"Hong","year":"2009","journal-title":"PLoS One"},{"key":"B25","doi-asserted-by":"publisher","first-page":"599","DOI":"10.3389\/fimmu.2016.00599","article-title":"Human C1q induces apoptosis in an ovarian cancer cell line via tumor necrosis factor pathway","volume":"7","author":"Kaur","year":"2016","journal-title":"Front. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1016\/j.it.2004.08.006","article-title":"C1q and tumor necrosis factor superfamily: Modularity and versatility","volume":"25","author":"Kishore","year":"2004","journal-title":"Trends Immunol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"398","DOI":"10.3389\/fimmu.2016.00398","article-title":"Editorial: State-of-the-Art research on C1q and the classical complement pathway","volume":"7","author":"Kishore","year":"2016","journal-title":"Front. Immunol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"317","DOI":"10.3389\/fimmu.2015.00317","article-title":"Emerging and novel functions of complement protein C1q","volume":"6","author":"Kouser","year":"2015","journal-title":"Front. Immunol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"510","DOI":"10.4149\/neo_2016_403","article-title":"Malignant melanoma: Diagnosis, treatment and cancer stem cells","volume":"63","author":"Kozovska","year":"2016","journal-title":"Neoplasma"},{"key":"B30","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1634\/theoncologist.2015-0522","article-title":"Prognosis of mucosal, uveal, acral, nonacral cutaneous, and unknown primary melanoma from the time of first metastasis","volume":"21","author":"Kuk","year":"2016","journal-title":"Oncologist"},{"key":"B31","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined nivolumab and ipilimumab or monotherapy in untreated melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.kint.2016.02.036","article-title":"Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury","volume":"90","author":"Laskowski","year":"2016","journal-title":"Kidney Int."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e108","DOI":"10.1158\/0008-5472.CAN-17-0307","article-title":"Timer: A web server for comprehensive analysis of tumor-infiltrating immune cells","volume":"77","author":"Li","year":"2017","journal-title":"Cancer Res."},{"key":"B34","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1007\/s11899-019-00523-x","article-title":"Tumor-infiltrating lymphocytes in the checkpoint inhibitor era","volume":"14","author":"Linette","year":"2019","journal-title":"Curr. Hematol. Malig. Rep."},{"key":"B35","doi-asserted-by":"publisher","first-page":"e20971","DOI":"10.1371\/journal.pone.0020971","article-title":"Transcriptome profiling of whole blood cells identifies PLEK2 and C1QB in human melanoma","volume":"6","author":"Luo","year":"2011","journal-title":"PLoS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"865","DOI":"10.3389\/fimmu.2019.00865","article-title":"Is the complement protein C1q a pro- or anti-tumorigenic factor? Bioinformatics analysis involving human carcinomas","volume":"10","author":"Mangogna","year":"2019","journal-title":"Front. Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2366","DOI":"10.3389\/fimmu.2019.02366","article-title":"Prognostic implications of the complement protein C1q in gliomas","volume":"10","author":"Mangogna","year":"2019","journal-title":"Front. Immunol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1177\/1753425910396252","article-title":"Complement and non-complement activating functions of C1q: A prototypical innate immune molecule","volume":"18","author":"Nayak","year":"2012","journal-title":"Innate Immun."},{"key":"B39","doi-asserted-by":"publisher","first-page":"5300","DOI":"10.1158\/1078-0432.CCR-13-0143","article-title":"CTLA-4 and PD-1\/PD-L1 blockade: New immunotherapeutic modalities with durable clinical benefit in melanoma patients","volume":"19","author":"Ott","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"B40","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1007\/s11864-016-0436-y","article-title":"Drug combinations as the new standard for melanoma treatment","volume":"17","author":"Polkowska","year":"2016","journal-title":"Curr. Treat. Options Oncol."},{"key":"B41","doi-asserted-by":"publisher","first-page":"S78","DOI":"10.1016\/j.jaad.2011.05.030","article-title":"Melanoma survival in the United States, 1992 to 2005","volume":"65","author":"Pollack","year":"2011","journal-title":"J. Am. Acad. Dermatol."},{"key":"B42","first-page":"1005","article-title":"Melanoma: Epidemiology, risk factors, pathogenesis, diagnosis and classification","volume":"28","author":"Rastrelli","year":"2014","journal-title":"Vivo"},{"key":"B43","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.trecan.2022.02.006","article-title":"C1q+ macrophages: Passengers or drivers of cancer progression","volume":"8","author":"Revel","year":"2022","journal-title":"Trends Cancer"},{"key":"B44","doi-asserted-by":"publisher","first-page":"4550","DOI":"10.1158\/1078-0432.CCR-11-0116","article-title":"Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy","volume":"17","author":"Rosenberg","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1158\/2326-6066.CIR-18-0891","article-title":"Tumor cells hijack macrophage-produced complement C1q to promote tumor growth","volume":"7","author":"Roumenina","year":"2019","journal-title":"Cancer Immunol. Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1038\/s41568-019-0210-0","article-title":"Context-dependent roles of complement in cancer","volume":"19","author":"Roumenina","year":"2019","journal-title":"Nat. Rev. Cancer"},{"key":"B47","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1016\/j.phrs.2016.07.017","article-title":"Vemurafenib resistance increases melanoma invasiveness and modulates the tumor microenvironment by MMP-2 upregulation","volume":"111","author":"Sandri","year":"2016","journal-title":"Pharmacol. Res."},{"key":"B48","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s13073-019-0647-5","article-title":"Prognostic value of B cells in cutaneous melanoma","volume":"11","author":"Selitsky","year":"2019","journal-title":"Genome Med."},{"key":"B49","doi-asserted-by":"publisher","first-page":"5916","DOI":"10.1002\/cam4.2373","article-title":"Inflammatory markers in intrahepatic cholangiocarcinoma: Effects of advanced liver disease","volume":"8","author":"Sellers","year":"2019","journal-title":"Cancer Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1007\/s12026-015-8705-6","article-title":"Fundamental role of C1q in autoimmunity and inflammation","volume":"63","author":"Son","year":"2015","journal-title":"Immunol. Res."},{"key":"B51","doi-asserted-by":"publisher","first-page":"5023","DOI":"10.1038\/s41467-019-12733-1","article-title":"A novel mouse model demonstrates that oncogenic melanocyte stem cells engender melanoma resembling human disease","volume":"10","author":"Sun","year":"2019","journal-title":"Nat. Commun."},{"key":"B52","doi-asserted-by":"publisher","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"W98","DOI":"10.1093\/nar\/gkx247","article-title":"Gepia: A web server for cancer and normal gene expression profiling and interactive analyses","volume":"45","author":"Tang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"B54","doi-asserted-by":"publisher","first-page":"568","DOI":"10.1038\/nature13954","article-title":"PD-1 blockade induces responses by inhibiting adaptive immune resistance","volume":"515","author":"Tumeh","year":"2014","journal-title":"Nature"},{"key":"B55","doi-asserted-by":"publisher","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"Uhlen","year":"2015","journal-title":"Science"},{"key":"B56","doi-asserted-by":"publisher","first-page":"5487","DOI":"10.1158\/1078-0432.CCR-16-0127","article-title":"Baseline biomarkers for outcome of melanoma patients treated with pembrolizumab","volume":"22","author":"Weide","year":"2016","journal-title":"Clin. Cancer Res."},{"key":"B57","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1056\/NEJMoa1302369","article-title":"Nivolumab plus ipilimumab in advanced melanoma","volume":"369","author":"Wolchok","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B58","doi-asserted-by":"publisher","first-page":"2442","DOI":"10.1158\/1078-0432.CCR-18-2652","article-title":"Multiplex quantitative analysis of tumor-infiltrating lymphocytes and immunotherapy outcome in metastatic melanoma","volume":"25","author":"Wong","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1812","DOI":"10.1080\/10428194.2018.1543883","article-title":"Is complement C1q a potential marker for tumor burden and immunodeficiency in multiple myeloma?","volume":"60","author":"Yang","year":"2019","journal-title":"Leuk. Lymphoma"}],"container-title":["Frontiers in Genetics"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.940306\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,30]],"date-time":"2022-08-30T09:24:14Z","timestamp":1661851454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fgene.2022.940306\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,30]]},"references-count":59,"alternative-id":["10.3389\/fgene.2022.940306"],"URL":"https:\/\/doi.org\/10.3389\/fgene.2022.940306","relation":{},"ISSN":["1664-8021"],"issn-type":[{"value":"1664-8021","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,30]]},"article-number":"940306"}}