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Open AccessArticle

Investigating Serum and Tissue Expression Identified a Cytokine/Chemokine Signature as a Highly Effective Melanoma Marker

1
Department of Civil Engineering and Computer Science Engineering, University of Rome Tor Vergata, 00133 Rome, Italy
2
Istituto Dermopatico dell’Immacolata, IDI-IRCCS, via Monti di Creta 104, 00167 Rome, Italy
3
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(12), 3680; https://doi.org/10.3390/cancers12123680
Received: 2 November 2020 / Revised: 26 November 2020 / Accepted: 4 December 2020 / Published: 8 December 2020
(This article belongs to the Special Issue Advances and Novel Treatment Options in Metastatic Melanoma)
In this study, we investigated the expression of 27 cytokines/chemokines in the serum of 232 individuals (136 melanoma patients vs. 96 controls). It identified several cytokines/chemokines differently expressed in melanoma patients as compared to the healthy controls, as a function of the presence of the melanoma, age, tumor thickness, and gender, indicating different systemic responses to the melanoma presence. We also analyzed the gene expression of the same 27 molecules at the tissue level in 511 individuals (melanoma patients vs. controls). From the gene expression analysis, we identified several cytokines/chemokines showing strongly different expression in melanoma as compared to the controls, and the 4-gene signature “IL-1Ra, IL-7, MIP-1a, and MIP-1b” as the best combination to discriminate melanoma samples from the controls, with an extremely high accuracy (AUC = 0.98). These data indicate the molecular mechanisms underlying melanoma setup and the relevant markers potentially useful to help the diagnosis of biopsy samples.
The identification of reliable and quantitative melanoma biomarkers may help an early diagnosis and may directly affect melanoma mortality and morbidity. The aim of the present study was to identify effective biomarkers by investigating the expression of 27 cytokines/chemokines in melanoma compared to healthy controls, both in serum and in tissue samples. Serum samples were from 232 patients recruited at the IDI-IRCCS hospital. Expression was quantified by xMAP technology, on 27 cytokines/chemokines, compared to the control sera. RNA expression data of the same 27 molecules were obtained from 511 melanoma- and healthy-tissue samples, from the GENT2 database. Statistical analysis involved a 3-step approach: analysis of the single-molecules by Mann–Whitney analysis; analysis of paired-molecules by Pearson correlation; and profile analysis by the machine learning algorithm Support Vector Machine (SVM). Single-molecule analysis of serum expression identified IL-1b, IL-6, IP-10, PDGF-BB, and RANTES differently expressed in melanoma (p < 0.05). Expression of IL-8, GM-CSF, MCP-1, and TNF-α was found to be significantly correlated with Breslow thickness. Eotaxin and MCP-1 were found differentially expressed in male vs. female patients. Tissue expression analysis identified very effective marker/predictor genes, namely, IL-1Ra, IL-7, MIP-1a, and MIP-1b, with individual AUC values of 0.88, 0.86, 0.93, 0.87, respectively. SVM analysis of the tissue expression data identified the combination of these four molecules as the most effective signature to discriminate melanoma patients (AUC = 0.98). Validation, using the GEPIA2 database on an additional 1019 independent samples, fully confirmed these observations. The present study demonstrates, for the first time, that the IL-1Ra, IL-7, MIP-1a, and MIP-1b gene signature discriminates melanoma from control tissues with extremely high efficacy. We therefore propose this 4-molecule combination as an effective melanoma marker. View Full-Text
Keywords: melanoma markers; cytokines; machine learning; Support Vector Machine; principal component analysis melanoma markers; cytokines; machine learning; Support Vector Machine; principal component analysis
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MDPI and ACS Style

Cesati, M.; Scatozza, F.; D’Arcangelo, D.; Antonini-Cappellini, G.C.; Rossi, S.; Tabolacci, C.; Nudo, M.; Palese, E.; Lembo, L.; Di Lella, G.; Facchiano, F.; Facchiano, A. Investigating Serum and Tissue Expression Identified a Cytokine/Chemokine Signature as a Highly Effective Melanoma Marker. Cancers 2020, 12, 3680. https://doi.org/10.3390/cancers12123680

AMA Style

Cesati M, Scatozza F, D’Arcangelo D, Antonini-Cappellini GC, Rossi S, Tabolacci C, Nudo M, Palese E, Lembo L, Di Lella G, Facchiano F, Facchiano A. Investigating Serum and Tissue Expression Identified a Cytokine/Chemokine Signature as a Highly Effective Melanoma Marker. Cancers. 2020; 12(12):3680. https://doi.org/10.3390/cancers12123680

Chicago/Turabian Style

Cesati, Marco; Scatozza, Francesca; D’Arcangelo, Daniela; Antonini-Cappellini, Gian C.; Rossi, Stefania; Tabolacci, Claudio; Nudo, Maurizio; Palese, Enzo; Lembo, Luigi; Di Lella, Giovanni; Facchiano, Francesco; Facchiano, Antonio. 2020. "Investigating Serum and Tissue Expression Identified a Cytokine/Chemokine Signature as a Highly Effective Melanoma Marker" Cancers 12, no. 12: 3680. https://doi.org/10.3390/cancers12123680

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