title: A gene expression inflammatory signature specifically predicts multiple myeloma evolution and patients survival.
abstract: Multiple myeloma (MM) is closely dependent on cross-talk between malignant plasma cells and cellular components of the inflammatory/immunosuppressive bone marrow milieu, which promotes disease progression, drug resistance, neo-angiogenesis, bone destruction and immune-impairment. We investigated the relevance of inflammatory genes in predicting disease evolution and patient survival. A bioinformatics study by Ingenuity Pathway Analysis on gene expression profiling dataset of monoclonal gammopathy of undetermined significance, smoldering and symptomatic-MM, identified inflammatory and cytokine/chemokine pathways as the most progressively affected during disease evolution. We then selected 20 candidate genes involved in B-cell inflammation and we investigated their role in predicting clinical outcome, through univariate and multivariate analyses (log-rank test, logistic regression and Cox-regression model). We defined an 8-genes signature (IL8, IL10, IL17A, CCL3, CCL5, VEGFA, EBI3 and NOS2) identifying each condition (MGUS/smoldering/symptomatic-MM) with 84% accuracy. Moreover, six genes (IFNG, IL2, LTA, CCL2, VEGFA, CCL3) were found independently correlated with patients' survival. Patients whose MM cells expressed high levels of Th1 cytokines (IFNG/LTA/IL2/CCL2) and low levels of CCL3 and VEGFA, experienced the longest survival. On these six genes, we built a prognostic risk score that was validated in three additional independent datasets. In this study, we provide proof-of-concept that inflammation has a critical role in MM patient progression and survival. The inflammatory-gene prognostic signature validated in different datasets clearly indicates novel opportunities for personalized anti-MM treatment.
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Botta
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
authors.forename: M T
authors.initials: MT
authors.lastname: Di Martino
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Ciliberto
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cucè
authors.affiliation: Department of Oncology, Siena University, Siena, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Correale
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Tagliaferri
authors.affiliation: Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Tassone
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019295:Computational Biology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D059467:Transcriptome / Q000235:genetics
chemical_list: D009363:Neoplasm Proteins