168 results on '"Rodolfo, Monica"'
Search Results
152. 3D culture of Erdheim-Chester disease tissues unveils histiocyte metabolism as a new therapeutic target
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Antonello Villa, Monica Rodolfo, Elisabetta Ferrero, Lorenzo Dagna, Giulio Cavalli, Marina Ferrarini, Maria Giulia Cangi, Claudio Doglioni, Daniela Belloni, Barbara Vergani, Riccardo Biavasco, Simone Cenci, Villa, Antonello, Belloni, Daniela, Vergani, Barbara, Cenci, Simone, Cavalli, Giulio, Biavasco, Riccardo, Rodolfo, Monica, Cangi, Maria Giulia, Doglioni, Claudio, Dagna, Lorenzo, Ferrero, Elisabetta, Ferrarini, Marina, Villa, A, Belloni, D, Vergani, B, Cenci, S, Cavalli, G, Biavasco, R, Rodolfo, M, Cangi, M, Doglioni, C, Dagna, L, Ferrero, E, and Ferrarini, M
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0301 basic medicine ,Erdheim-Chester Disease ,Letter ,medicine.medical_treatment ,Immunology ,General Biochemistry, Genetics and Molecular Biology ,Proinflammatory cytokine ,Tissue Culture Techniques ,03 medical and health sciences ,0302 clinical medicine ,Bioreactors ,Rheumatology ,medicine ,Humans ,Immunology and Allergy ,Molecular Targeted Therapy ,Vemurafenib ,Protein Kinase Inhibitors ,Histiocyte ,030203 arthritis & rheumatology ,Biochemistry, Genetics and Molecular Biology (all) ,CD68 ,business.industry ,Histiocytes ,medicine.disease ,Infliximab ,Histiocytosis ,030104 developmental biology ,Cytokine ,Erdheim–Chester disease ,Cancer research ,business ,medicine.drug - Abstract
Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis, characterised by tissue infiltration by foamy CD68+ CD1a− histiocytes.1 The disease has pleomorphic clinical manifestations, including long bones and extraskeletal involvement, and may be life-threatening, particularly when heart and central nervous system are affected.1 ECD histiocytes secrete proinflammatory cytokines2 and carry activating mutations along the RAS-RAF-MEK-ERK protein kinase signalling pathway, most commonly the BRAFV600E oncogenic mutation.3 4 Accordingly, patients with ECD have been treated with cytokine inhibitors, including infliximab,1 ,5 and, more recently, with the BRAFV600E inhibitor vemurafenib.6 The latter, however, induces sustained but partial clinical responses and recurrences on discontinuation,6 underlining the need for more effective therapeutic strategies. To identify the outcomes downstream constitutive ERK phosphorylation in ECD histiocytes and their response to small molecule-based inhibition, we performed three-dimensional (3D) culture of tissues from three BRAFV600E-mutated ECD patients in the RCCS bioreactor7 (and online supplementary methods) in the presence/absence of vemurafenib or infliximab, used as control.### Supplementary data [annrheumdis-2018-214432supp001.pdf] All patient samples maintained production of prototypical cytokines and chemokines2 in bioreactor, thus validating this technology also for ECD; moreover, infliximab, and, to a lesser degree, vemurafenib, significantly decreased cyto-chemokines …
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- 2018
153. The density and spatial tissue distribution of CD8 + and CD163 + immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors.
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Massi D, Rulli E, Cossa M, Valeri B, Rodolfo M, Merelli B, De Logu F, Nassini R, Del Vecchio M, Di Guardo L, De Penni R, Guida M, Sileni VC, Di Giacomo AM, Tucci M, Occelli M, Portelli F, Vallacchi V, Consoli F, Quaglino P, Queirolo P, Baroni G, Carnevale-Schianca F, Cattaneo L, Minisini A, Palmieri G, Rivoltini L, and Mandalà M
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- Aged, Antigens, CD immunology, Antigens, Differentiation, Myelomonocytic immunology, B7-H1 Antigen immunology, CD8 Antigens immunology, Female, Humans, Kaplan-Meier Estimate, Male, Melanoma mortality, Middle Aged, Programmed Cell Death 1 Ligand 2 Protein immunology, Receptors, Cell Surface immunology, Tumor Microenvironment immunology, beta Catenin immunology, MAP Kinase Kinase Kinases antagonists & inhibitors, Melanoma drug therapy, Melanoma immunology, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins B-raf antagonists & inhibitors
- Abstract
Background: Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors., Methods: Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received., Results: Patients with high intratumoral, but not peritumoral, CD8
+ T cells and concomitantly low CD163+ myeloid cells displayed higher probability of response (OR 9.91, 95% CI 2.23-44.0, p = 0.003) and longer overall survival (HR 0.34, 95% CI 0.16-0.72, p = 0.005) compared to those with intratumoral low CD8+ T cells and high CD163+ myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor β-catenin overexpression showed association with lower probability of response (OR 0.48, 95% CI 0.21-1.06, p = 0.068)., Conclusions: Analysis of the spatially constrained distribution of CD8+ and CD163+ cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways.- Published
- 2019
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154. MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort.
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Pellegrini C, Botta F, Massi D, Martorelli C, Facchetti F, Gandini S, Maisonneuve P, Avril MF, Demenais F, Bressac-de Paillerets B, Hoiom V, Cust AE, Anton-Culver H, Gruber SB, Gallagher RP, Marrett L, Zanetti R, Dwyer T, Thomas NE, Begg CB, Berwick M, Puig S, Potrony M, Nagore E, Ghiorzo P, Menin C, Manganoni AM, Rodolfo M, Brugnara S, Passoni E, Sekulovic LK, Baldini F, Guida G, Stratigos A, Ozdemir F, Ayala F, Fernandez-de-Misa R, Quaglino P, Ribas G, Romanini A, Migliano E, Stanganelli I, Kanetsky PA, Pizzichetta MA, García-Borrón JC, Nan H, Landi MT, Little J, Newton-Bishop J, Sera F, Fargnoli MC, and Raimondi S
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- Adolescent, Adult, Aged, Case-Control Studies, Child, Female, Genetic Predisposition to Disease, Humans, Logistic Models, Male, Middle Aged, Odds Ratio, Polymorphism, Genetic, Retrospective Studies, Biomarkers, Tumor genetics, Germ-Line Mutation, Melanoma genetics, Receptor, Melanocortin, Type 1 genetics, Skin Neoplasms genetics
- Abstract
Background: Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls., Methods: In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger., Findings: We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02-2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06-3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05-2·44; p=0·04) and Asp294His (2·15, 1·05-4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants., Interpretation: Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies., Funding: SPD-Pilot/Project-Award-2015; AIRC-MFAG-11831., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
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- 2019
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155. Immunosuppressive circuits in tumor microenvironment and their influence on cancer treatment efficacy.
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Tuccitto A, Shahaj E, Vergani E, Ferro S, Huber V, Rodolfo M, Castelli C, Rivoltini L, and Vallacchi V
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- Animals, Humans, Immunotherapy methods, Neoplasms immunology, Tumor Escape immunology, Tumor Microenvironment immunology
- Abstract
It has been for long conceived that hallmarks of cancer were intrinsic genetic features driving tumor development, proliferation, and progression, and that targeting such cell-autonomous pathways could be sufficient to achieve therapeutic cancer control. Clinical ex vivo data demonstrated that treatment efficacy often relied on the contribution of host immune responses, hence introducing the concept of tumor microenvironment (TME), namely the existence, along with tumor cells, of non-tumor components that could significantly influence tumor growth and survival. Among the complex network of TME-driving forces, immunity plays a key role and the balance between antitumor and protumor immune responses is a major driver in contrasting or promoting cancer spreading. TME is usually a very immunosuppressed milieu because of a vast array of local alterations contrasting antitumor adaptive immunity, where metabolic changes contribute to cancer dissemination by impairing T cell infiltration and favoring the accrual and activation of regulatory cells. Subcellular structures known as extracellular vesicles then help spreading immunosuppression at systemic levels by distributing genetic and protein tumor repertoire in distant tissues. A major improvement in the knowledge of TME is now pointing the attention back to tumor cells; indeed, recent findings are showing how oncogenic pathways and specific mutations in tumor cells can actually dictate the nature and the function of immune infiltrate. As our information on the reciprocal interactions regulating TME increases, finding a strategy to interfere with TME crosstalk becomes more complex and challenging. Nevertheless, TME interactions represent a promising field for the discovery of novel biomarkers and therapeutic targets for improving treatment efficacy in cancer.
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- 2019
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156. Tumor-derived microRNAs induce myeloid suppressor cells and predict immunotherapy resistance in melanoma.
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Huber V, Vallacchi V, Fleming V, Hu X, Cova A, Dugo M, Shahaj E, Sulsenti R, Vergani E, Filipazzi P, De Laurentiis A, Lalli L, Di Guardo L, Patuzzo R, Vergani B, Casiraghi E, Cossa M, Gualeni A, Bollati V, Arienti F, De Braud F, Mariani L, Villa A, Altevogt P, Umansky V, Rodolfo M, and Rivoltini L
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- Animals, Female, Humans, Leukocytes, Mononuclear pathology, Male, Melanoma, Experimental pathology, Melanoma, Experimental therapy, Mice, Myeloid-Derived Suppressor Cells pathology, Immunotherapy, Leukocytes, Mononuclear immunology, Melanoma, Experimental immunology, MicroRNAs metabolism, Myeloid-Derived Suppressor Cells immunology, RNA, Neoplasm immunology
- Abstract
The accrual of myeloid-derived suppressor cells (MDSCs) represents a major obstacle to effective immunotherapy in cancer patients, but the mechanisms underlying this process in the human setting remain elusive. Here, we describe a set of microRNAs (miR-146a, miR-155, miR-125b, miR-100, let-7e, miR-125a, miR-146b, miR-99b) that are associated with MDSCs and resistance to treatment with immune checkpoint inhibitors in melanoma patients. The miRs were identified by transcriptional analyses as being responsible for the conversion of monocytes into MDSCs (CD14+HLA-DRneg cells) mediated by melanoma extracellular vesicles (EVs) and were shown to recreate MDSC features upon transfection. In melanoma patients, these miRs were increased in circulating CD14+ monocytes, plasma, and tumor samples, where they correlated with the myeloid cell infiltrate. In plasma, their baseline levels clustered with the clinical efficacy of CTLA-4 or programmed cell death protein 1 (PD-1) blockade. Hence, MDSC-related miRs represent an indicator of MDSC activity in cancer patients and a potential blood marker of a poor immunotherapy outcome.
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- 2018
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157. Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup.
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Bruno W, Pastorino L, Ghiorzo P, Andreotti V, Martinuzzi C, Menin C, Elefanti L, Stagni C, Vecchiato A, Rodolfo M, Maurichi A, Manoukian S, De Giorgi V, Savarese I, Gensini F, Borgognoni L, Testori A, Spadola G, Mandalà M, Imberti G, Savoia P, Astrua C, Ronco AM, Farnetti A, Tibiletti MG, Lombardo M, Palmieri G, Ayala F, Ascierto P, Ghigliotti G, Muggianu M, Spagnolo F, Picasso V, Tanda ET, Queirolo P, and Bianchi-Scarrà G
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- Adolescent, Adult, Aged, Aged, 80 and over, Cyclin-Dependent Kinase 4 genetics, Cyclin-Dependent Kinase Inhibitor p16 genetics, Germ-Line Mutation, Humans, Italy, Microphthalmia-Associated Transcription Factor genetics, Middle Aged, Mutation Rate, Young Adult, Genetic Counseling, Melanoma genetics, Neoplasms, Multiple Primary genetics, Patient Selection, Skin Neoplasms genetics
- Abstract
Background: Multiple primary melanoma (MPM), in concert with a positive family history, is a predictor of cyclin-dependent kinase (CDK) inhibitor 2A (CDKN2A) germline mutations. A rule regarding the presence of either 2 or 3 or more cancer events (melanoma and pancreatic cancer) in low or high melanoma incidence populations, respectively, has been established to select patients for genetic referral., Objective: We sought to determine the CDKN2A/CDK4/microphthalmia-associated transcription factor mutation rate among Italian patients with MPM to appropriately direct genetic counseling regardless of family history., Methods: In all, 587 patients with MPM and an equal number with single primary melanomas and control subjects were consecutively enrolled at the participating centers and tested for CDKN2A, CDK4, and microphthalmia-associated transcription factor., Results: CDKN2A germline mutations were found in 19% of patients with MPM versus 4.4% of patients with single primary melanoma. In familial MPM cases the mutation rate varied from 36.6% to 58.8%, whereas in sporadic MPM cases it varied from 8.2% to 17.6% in patients with 2 and 3 or more melanomas, respectively. The microphthalmia-associated transcription factor E318K mutation accounted for 3% of MPM cases altogether., Limitations: The study was hospital based, not population based. Rare novel susceptibility genes were not tested., Conclusion: Italian patients who developed 2 melanomas, even in situ, should be referred for genetic counseling even in the absence of family history., (Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)
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- 2016
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158. Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b.
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Vergani E, Di Guardo L, Dugo M, Rigoletto S, Tragni G, Ruggeri R, Perrone F, Tamborini E, Gloghini A, Arienti F, Vergani B, Deho P, De Cecco L, Vallacchi V, Frati P, Shahaj E, Villa A, Santinami M, De Braud F, Rivoltini L, and Rodolfo M
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- Adult, Aged, Blotting, Western, Case-Control Studies, Chemokine CCL2 genetics, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Male, Melanoma drug therapy, Melanoma metabolism, Melanoma pathology, Middle Aged, Neoplasm Staging, Prognosis, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Tumor Cells, Cultured, Vemurafenib, Chemokine CCL2 metabolism, Drug Resistance, Neoplasm genetics, Indoles pharmacology, Melanoma genetics, MicroRNAs genetics, Sulfonamides pharmacology
- Abstract
In melanoma, the adaptative cell response to BRAF inhibitors includes altered patterns of cytokine production contributing to tumor progression and drug resistance. Among the factors produced by PLX4032-resistant melanoma cell lines, CCL2 was higher compared to the sensitive parental cell lines and increased upon drug treatment. CCL2 acted as an autocrine growth factor for melanoma cells, stimulating the proliferation and resistance to apoptosis. In patients, CCL2 is detected in melanoma cells in tumors and in plasma at levels that correlate with tumor burden and lactate dehydrogenase. Vemurafenib treatment increased the CCL2 levels in plasma, whereas the long-term clinical response was associated with low CCL2 levels.Increased CCL2 production was associated with miRNA deregulation in the resistant cells. miR-34a, miR-100 and miR-125b showed high expression in both resistant cells and in tumor biopsies that were obtained from treated patients, and they were involved in the control of cell proliferation and apoptosis. Inhibition of CCL2 and of the selected miRNAs restored both the cell apoptosis and the drug efficacy in resistant melanoma cells. Therefore, CCL2 and miRNAs are potential prognostic factors and attractive targets for counteracting treatment resistance in metastatic melanoma.
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- 2016
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159. Association of microRNA 146a polymorphism rs2910164 and the risk of melanoma in an Italian population.
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Gomez-Lira M, Ferronato S, Orlandi E, Dal Molin A, Malerba G, Frigerio S, Rodolfo M, and Romanelli MG
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- Adult, Case-Control Studies, Female, Gene Frequency, Genotype, Humans, Italy, Male, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Sex Factors, Melanoma genetics, MicroRNAs genetics, Skin Neoplasms genetics
- Published
- 2015
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160. Modulation of the myeloid compartment of the immune system by angiogenic- and kinase inhibitor-targeted anti-cancer therapies.
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Castelli C, Rivoltini L, Rodolfo M, Tazzari M, Belgiovine C, and Allavena P
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- Animals, Humans, Melanoma drug therapy, Sarcoma drug therapy, Angiogenesis Inhibitors therapeutic use, Antineoplastic Agents therapeutic use, Melanoma immunology, Myeloid Cells drug effects, Protein Kinase Inhibitors therapeutic use, Sarcoma immunology
- Abstract
Targeted therapies were rationally designed to inhibit molecular pathways in tumor cells critically involved in growth and survival; however, many drugs used in targeted therapies may affect the immune system. In addition, selected conventional chemotherapeutic agents have also been reported to be endowed with direct or indirect effects on immunity, for instance via immunogenic death of tumors. Thus, cancer therapies may have off-target effects, some of which are directed to the immune system. Here, we will review some of these effects in specific therapeutic approaches. We will examine the modulation of the immune contexture in human sarcoma and melanoma induced by anti-angiogenic therapies and by BRAF inhibitors, respectively. We will then discuss how the anti-tumor agent trabectedin is selectively cytotoxic to cells of the monocytic-macrophage lineage and how these immune-related effects can be part of the response to treatment.
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- 2015
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161. Association of promoter polymorphism -765G>C in the PTGS2 gene with malignant melanoma in Italian patients and its correlation to gene expression in dermal fibroblasts.
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Gomez-Lira M, Ferronato S, Malerba G, Santinami M, Maurichi A, Sangalli A, Turco A, Perego P, and Rodolfo M
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- Adult, Aged, Case-Control Studies, Female, Fibroblasts enzymology, Gene Expression, Haplotypes, Humans, Italy, Male, Middle Aged, Promoter Regions, Genetic, Skin enzymology, Cyclooxygenase 2 genetics, Melanoma enzymology, Melanoma genetics, Polymorphism, Single Nucleotide, Skin Neoplasms enzymology, Skin Neoplasms genetics
- Abstract
Prostaglandins, especially prostaglandin E synthetase (PGE2), influence carcinogenesis by promoting cell proliferation, inhibiting apoptosis, stimulating angiogenesis and mediating immune suppression. Cyclooxygenase-2, coded by the PTGS2 gene, is the key enzyme in the production of prostaglandins. In melanoma, Cox-2 is over expressed in primary malignant melanoma (MM) and in their corresponding metastases. Polymorphisms in the promoter region of PTGS2 gene can modulate gene expression and could modify individual susceptibility to MM. Two hundred and forty melanoma patients and 342 controls were genotyped for polymorphisms -765G>C (rs20417) and -1195A>G (rs689466). Allele -765C frequency was significantly higher in melanoma patients. No allele frequency differences for -1195A>G polymorphism were observed. Haplotype analysis revealed that the haplotypes carrying the minor alleles were associated to a higher risk of melanoma (P = 0.02). Expression analysis showed that allele -765C is associated to a higher gene expression and could represent a risk allele by affecting the functionality of the promoter., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
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162. Malignant and benign tumors associated with multiple primary melanomas: just the starting block for the involvement of MITF, PTEN and CDKN2A in multiple cancerogenesis?
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Pollio A, Tomasi A, Seidenari S, Pellacani G, Rodolfo M, Frigerio S, Maurichi A, Turchetti D, Bassoli S, Ruini C, and Ponti G
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- Adult, Aged, 80 and over, Carcinogenesis genetics, Female, Germ-Line Mutation genetics, Humans, Male, Melanoma genetics, Middle Aged, Neoplasms, Multiple Primary genetics, Pedigree, Phenotype, Skin Neoplasms genetics, Carcinogenesis pathology, Cyclin-Dependent Kinase Inhibitor p16 genetics, Melanoma pathology, Microphthalmia-Associated Transcription Factor genetics, Neoplasms, Multiple Primary pathology, PTEN Phosphohydrolase genetics, Skin Neoplasms pathology
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- 2013
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163. CDKN2A and MC1R variants influence dermoscopic and confocal features of benign melanocytic lesions in multiple melanoma patients.
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Bassoli S, Maurichi A, Rodolfo M, Casari A, Frigerio S, Pupelli G, Farnetani F, Pelosi G, Santinami M, and Pellacani G
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- Adult, Case-Control Studies, DNA Mutational Analysis, Dermoscopy, Female, Heterozygote, Humans, Male, Melanoma diagnosis, Melanoma pathology, Microscopy, Confocal, Nevus diagnosis, Nevus pathology, Pigmentation, Prospective Studies, Cyclin-Dependent Kinase Inhibitor p16 genetics, Melanocytes cytology, Melanoma genetics, Mutation, Nevus genetics, Receptor, Melanocortin, Type 1 genetics
- Abstract
Non-invasive diagnostic tools are effective in the histomorphological study of melanocytic lesions. The role of melanoma susceptibility genes on melanocytic nevi histopathological features is not clear. The current study aimed to correlate genetic alterations and histomorphological features of melanocytic nevi. Clinical, dermoscopic and confocal features of 34 multiple melanoma patients and 34 controls were compared. Among patients with melanoma, carriers of CDKN2A mutations and/or MC1R variants, and wild-type genes were also compared. In patients with melanoma, a lighter phototype (P = 0.051), a higher number of nevi (P < 0.01) and clinically atypical nevi (P < 0.01) were observed. At dermoscopy, these nevi showed a complex pattern (P = 0.011), atypical network (P = 0.018) and irregular pigmentation (P = 0.037); at confocal, an irregular meshwork pattern (P = 0.026) with atypical nests (P = 0.016) and an inflammatory infiltrate (P = 0.048) were observed. Among patients with melanoma genetically tested, CDKN2A G101W mutation carriers were more frequently younger (P = 0.023), with clinically atypical nevi (P = 0.050), with cytological atypia (P = 0.033) at confocal. G101W mutation and MC1R variants carriers showed hypopigmented nevi (P = 0.002) and, at confocal, roundish cells infiltrating the junction (P = 0.019). These data suggest an influence of CDKN2A mutation and MC1R variants in the development of dysplastic melanocytic lesions. Non-invasive histomorphological evaluation, together with genetic studies, improves melanoma risk identification and early diagnosis, for a patient-tailored management., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2013
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164. A variant in FTO shows association with melanoma risk not due to BMI.
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Iles MM, Law MH, Stacey SN, Han J, Fang S, Pfeiffer R, Harland M, Macgregor S, Taylor JC, Aben KK, Akslen LA, Avril MF, Azizi E, Bakker B, Benediktsdottir KR, Bergman W, Scarrà GB, Brown KM, Calista D, Chaudru V, Fargnoli MC, Cust AE, Demenais F, de Waal AC, Dębniak T, Elder DE, Friedman E, Galan P, Ghiorzo P, Gillanders EM, Goldstein AM, Gruis NA, Hansson J, Helsing P, Hočevar M, Höiom V, Hopper JL, Ingvar C, Janssen M, Jenkins MA, Kanetsky PA, Kiemeney LA, Lang J, Lathrop GM, Leachman S, Lee JE, Lubiński J, Mackie RM, Mann GJ, Martin NG, Mayordomo JI, Molven A, Mulder S, Nagore E, Novaković S, Okamoto I, Olafsson JH, Olsson H, Pehamberger H, Peris K, Grasa MP, Planelles D, Puig S, Puig-Butille JA, Randerson-Moor J, Requena C, Rivoltini L, Rodolfo M, Santinami M, Sigurgeirsson B, Snowden H, Song F, Sulem P, Thorisdottir K, Tuominen R, Van Belle P, van der Stoep N, van Rossum MM, Wei Q, Wendt J, Zelenika D, Zhang M, Landi MT, Thorleifsson G, Bishop DT, Amos CI, Hayward NK, Stefansson K, Bishop JA, and Barrett JH
- Subjects
- Alpha-Ketoglutarate-Dependent Dioxygenase FTO, Case-Control Studies, Cooperative Behavior, Female, Genome-Wide Association Study, Genotype, Humans, Meta-Analysis as Topic, Obesity, Risk Factors, Body Mass Index, Genetic Loci genetics, Genetic Predisposition to Disease, Melanoma etiology, Polymorphism, Single Nucleotide genetics, Proteins genetics
- Abstract
We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
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- 2013
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165. Clinical genetic testing for familial melanoma in Italy: a cooperative study.
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Bruno W, Ghiorzo P, Battistuzzi L, Ascierto PA, Barile M, Gargiulo S, Gensini F, Gliori S, Guida M, Lombardo M, Manoukian S, Menin C, Nasti S, Origone P, Pasini B, Pastorino L, Peissel B, Pizzichetta MA, Queirolo P, Rodolfo M, Romanini A, Scaini MC, Testori A, Tibiletti MG, Turchetti D, Leachman SA, and Bianchi Scarrà G
- Subjects
- Gene Frequency, Genetic Counseling, Humans, Italy epidemiology, Melanoma epidemiology, Neoplasms, Multiple Primary epidemiology, Neoplasms, Multiple Primary genetics, Point Mutation, Skin Neoplasms epidemiology, Cyclin-Dependent Kinase Inhibitor p16 genetics, Family Health, Genetic Testing, Melanoma genetics, Skin Neoplasms genetics
- Abstract
Background: The Italian Society of Human Genetics' (SIGU) recommendations on genetic counseling and testing for hereditary melanoma state that clinical genetic testing can be offered to Italian melanoma families with at least two affected members., Objective: In the framework of a cooperative study, we sought to establish the frequency of cyclin-dependent kinase inhibitor 2A mutations in melanoma families that underwent clinical genetic counseling and testing in accordance with the SIGU recommendations at 9 centers in different Italian regions., Methods: Cyclin-dependent kinase inhibitor 2A testing was conducted by direct sequencing and multiplex ligation-dependent probe amplification analysis in melanoma families with at least two affected members., Results: A total of 33% (68/204) of the families harbored cyclin-dependent kinase inhibitor 2A mutations. In the 145 families with two affected members the mutation frequency was 25%. Three novel mutations, L94P, A86T, and c.407dupG, were identified among the cases and not in 200 controls., Limitations: We were unable to perform separate analyses for individual centers, as in some cases the number of families was too small., Conclusions: The availability of clinical genetic testing for melanoma to families with just two affected members in the same branch is justified in Italy in terms of the likelihood of identifying a mutation.
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- 2009
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166. MAGE-A tumor antigens target p53 transactivation function through histone deacetylase recruitment and confer resistance to chemotherapeutic agents.
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Monte M, Simonatto M, Peche LY, Bublik DR, Gobessi S, Pierotti MA, Rodolfo M, and Schneider C
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- Apoptosis, Cell Line, Tumor, DNA Damage, Histone Deacetylases chemistry, Humans, Hydroxamic Acids pharmacology, Melanoma metabolism, Melanoma-Specific Antigens metabolism, Protein Structure, Tertiary, Antigens, Neoplasm physiology, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Histone Deacetylases metabolism, Melanoma-Specific Antigens biosynthesis, Neoplasm Proteins biosynthesis, Neoplasm Proteins metabolism, Transcriptional Activation, Tumor Suppressor Protein p53 metabolism
- Abstract
The MAGE gene family is characterized by a conserved domain (MAGE Homology Domain). A subset of highly homologous MAGE genes (group A; MAGE-A) belong to the chromosome X-clustered cancer/testis antigens. MAGE-A genes are normally expressed in the human germ line and overexpressed in various tumor types; however, their biological function is largely unknown. Here we present evidence indicating that MageA2 protein, belonging to the MAGE-A subfamily, confers wild-type-p53-sensitive resistance to etoposide (ET) by inducing a novel p53 inhibitory loop involving recruitment of histone deacetylase 3 (HDAC3) to MageA2/p53 complex, thus strongly down-regulating p53 transactivation function. In fact, enhanced MageA2 protein levels, in addition to ET resistance, correlate with impaired acetylation of both p53 and histones surrounding p53-binding sites. Association between MAGE-A expression levels and resistance to ET treatment is clearly shown in short-term cell lines obtained from melanoma biopsies harboring wild-type-p53, whereas cells naturally, or siRNA-mediated expressing low MAGE-A levels, correlate with enhanced p53-dependent sensitivity to ET. In addition, combined trichostatin A/ET treatment in melanoma cells expressing high MAGE-A levels reestablishes p53 response and reverts the chemoresistance.
- Published
- 2006
- Full Text
- View/download PDF
167. BRAF alterations are associated with complex mutational profiles in malignant melanoma.
- Author
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Daniotti M, Oggionni M, Ranzani T, Vallacchi V, Campi V, Di Stasi D, Torre GD, Perrone F, Luoni C, Suardi S, Frattini M, Pilotti S, Anichini A, Tragni G, Parmiani G, Pierotti MA, and Rodolfo M
- Subjects
- Adult, Aged, Aged, 80 and over, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinases genetics, Female, Genes, p16, Genes, p53, Humans, Male, Melanoma etiology, Melanoma mortality, Middle Aged, PTEN Phosphohydrolase, Phosphoric Monoester Hydrolases genetics, Promoter Regions, Genetic, Proto-Oncogene Proteins B-raf, Tumor Suppressor Proteins genetics, Melanoma genetics, Mutation, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-raf genetics
- Abstract
To evaluate the mutational profiles associated with BRAF mutations in human melanoma, we have studied BRAF, RAS, PTEN, TP53, CDKN2A and CDK4 genes and their expression in melanoma lesions. Owing to the lack of sufficient material from fresh specimens, we employed short-term cell lines obtained from melanoma biopsies. In all, 41 melanoma obtained from eight primary lesions, 20 nodal, 11 cutaneous and two visceral metastases from patients with sporadic (n=31), familial (n=4) and multiple melanoma (n=2) were analysed. The results revealed novel missense mutations in the BRAF, PTEN, CDKN2A and CDK4 genes. Overall, activating mutations of BRAF and loss of functional p16 and ARF were detected in the majority of melanomas (29/41, 36/41 and 29/41, respectively), while PTEN alterations/loss, NRAS and TP53 mutations occurred less frequently (6/41, 6/41 and 10/41, respectively). In the resulting 12 mutational profiles, p16/ARF loss associated with mutated BRAFV599E was the most represented (n=15). In addition, TP53 and PTEN mutations were always accompanied with BRAF alterations, while PTEN loss was found in association with CDKN2A or TP53 mutations in the absence of BRAF activation. The p16/ARFDelta+BRAF/RAS profile was significantly associated with a longer survival, while complex mutational profiles were detected in highly aggressive disease and poor survival. These data support the existence of several molecularly defined melanoma groups which likely reflect different clinical/biological behaviour, thus suggesting that a more extensive molecular classification of melanoma would significantly impact its clinical management.
- Published
- 2004
- Full Text
- View/download PDF
168. Antigen-specific immunity in neuroblastoma patients: antibody and T-cell recognition of NY-ESO-1 tumor antigen.
- Author
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Rodolfo M, Luksch R, Stockert E, Chen YT, Collini P, Ranzani T, Lombardo C, Dalerba P, Rivoltini L, Arienti F, Fossati-Bellani F, Old LJ, Parmiani G, and Castelli C
- Subjects
- Cell Line, Tumor, HLA-A2 Antigen immunology, Humans, Immunoglobulin G biosynthesis, Immunoglobulin G blood, Immunohistochemistry, Lymphocyte Activation immunology, Peptide Fragments immunology, Protein Biosynthesis, Proteins genetics, Reverse Transcriptase Polymerase Chain Reaction, Antigens, Neoplasm, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Epitopes, T-Lymphocyte immunology, Membrane Proteins, Neuroblastoma immunology, Proteins immunology, T-Lymphocytes immunology
- Abstract
Neuroblastoma cells have been shown to express molecularly defined tumor-associated antigens, which could represent potential targets of T and/or B cell-mediated immunity. However, the existence of a spontaneous immune response to such tumor antigens in neuroblastoma patients has yet to be investigated. In the present work we addressed the issue of whether NY-ESO-1, a germ cell antigen aberrantly expressed in different tumor types, is expressed by neuroblastoma cells and may represent a target for humoral and/or cellular immune responses in neuroblastoma patients. We found that a large fraction of neuroblastoma biopsies, independently from the clinical stage and degree of tumor cell differentiation, expressed significant levels of NY-ESO-1 as assessed by reverse transcription-PCR and immunohistochemistry. NY-ESO-1-specific IgG antibodies were detected in the sera of 10% of neuroblastoma patients with stage III or IV disease, but not in patients in clinical remission or with earlier stages. This suggests that antibody production occurred as a late event in the course of disease. NY-ESO-1-specific immune responses were observed for CD4(+) and CD8(+) T cells from peripheral blood lymphocytes in 4 of 8 neuroblastoma patients, as detected by IFN-gamma enzyme-linked immunospot assay after in vitro stimulation either with the NY-ESO-1 recombinant protein or with the HLA-A2-restricted peptide NY-ESO-1(157-167). NY-ESO-1-specific CD4(+) and CD8(+) T cells were also able to recognize NY-ESO-1 expressing neuroblastoma cells. The presence of T cells specific for NY-ESO-1 antigen was not associated with the stage of disease, or to the presence or absence of NY-ESO-1 specific antibodies. We conclude that NY-ESO-1 is an immunogenic antigen in neuroblastoma patients and represents a candidate target for immune-based therapy.
- Published
- 2003
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