RESUMO
Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasm. Patients are usually diagnosed when current treatments have limited benefits, highlighting the need for noninvasive tests aimed at an MPM risk assessment tool that might improve life expectancy. Three hundred asbestos-exposed subjects (163 MPM cases and 137 cancer-free controls), from the same geographical region in Italy, were recruited. The evaluation of asbestos exposure was conducted considering the frequency, the duration and the intensity of occupational, environmental and domestic exposure. A genome-wide methylation array was performed to identify novel blood DNA methylation (DNAm) markers of MPM. Multiple regression analyses adjusting for potential confounding factors and interaction between asbestos exposure and DNAm on the MPM odds ratio were applied. Epigenome-wide analysis (EWAS) revealed 12 single-CpGs associated with the disease. Two of these showed high statistical power (99%) and effect size (>0.05) after false discovery rate (FDR) multiple comparison corrections: (i) cg03546163 in FKBP5, significantly hypomethylated in cases (Mean Difference in beta values (MD) = -0.09, 95% CI = -0.12|-0.06, p = 1.2 × 10-7), and (ii) cg06633438 in MLLT1, statistically hypermethylated in cases (MD = 0.07, 95% CI = 0.04|0.10, p = 1.0 × 10-6). Based on the interaction analysis, asbestos exposure and epigenetic profile together may improve MPM risk assessment. Above-median asbestos exposure and hypomethylation of cg03546163 in FKBP5 (OR = 20.84, 95% CI = 8.71|53.96, p = 5.5 × 10-11) and hypermethylation of cg06633438 in MLLT1 (OR = 11.71, 95% CI = 4.97|29.64, p = 5.9 × 10-8) genes compared to below-median asbestos exposure and hyper/hypomethylation of single-CpG DNAm, respectively. Receiver Operation Characteristics (ROC) for Case-Control Discrimination showed a significant increase in MPM discrimination when DNAm information was added in the model (baseline model, BM: asbestos exposure, age, gender and white blood cells); area under the curve, AUC = 0.75; BM + cg03546163 at FKBP5. AUC = 0.89, 2.1 × 10-7; BM + cg06633438 at MLLT1. AUC = 0.89, 6.3 × 10-8. Validation and replication procedures, considering independent sample size and a different DNAm analysis technique, confirmed the observed associations. Our results suggest the potential application of DNAm profiles in blood to develop noninvasive tests for MPM risk assessment in asbestos-exposed subjects.
RESUMO
Pleural effusions are among the first clinical manifestations of malignant pleural mesothelioma (MPM) and often constitute the only available material for diagnosis. Although an MPM diagnosis can be reliable on cytology, the reported sensitivity is low (30% to 75%). Particularly, it can be hard to discriminate epithelioid MPM, the most common histotype, from reactive mesothelial hyperplasia (MH). Currently, BRCA1-associated protein 1 (BAP1) and CDKN2A (p16), evaluated by immunohistochemistry and fluorescent in situ hybridization, respectively, are the most valuable markers to discriminate MPM and MH. Both markers have a high specificity, but their sensitivity is not always satisfying, even when used together. We have recently developed a 117-gene expression panel, based on Nanostring technology, able to differentiate epithelioid MPM from MH pleural tissues better than BAP1 and p16. Herein, we evaluated the efficacy of the same panel on an independent retrospective cohort of 23 MPM and 11 MH pleural effusions (cell blocks and smears). The overall sensitivity and specificity of the panel were equal to 0.9565 and 1, respectively. Moreover, the panel performance was compared with BAP1 and p16 on 25 cell blocks. Sensitivity levels of gene panel, BAP1 alone, p16 alone, and BAP1 plus p16 were 1, 0.5882, 0.4706, and 0.7647, respectively. Specificity was always 1. Although further validation is needed, this gene panel could really facilitate patients' management, allowing a definitive MPM diagnosis directly on pleural effusions.
Assuntos
Mesotelioma Maligno/diagnóstico , Neoplasias Pleurais/diagnóstico , Idoso , Biomarcadores Tumorais , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Citodiagnóstico , Diagnóstico Diferencial , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Masculino , Mesotelioma Maligno/genética , Pessoa de Meia-Idade , Neoplasias Pleurais/genética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismoRESUMO
BACKGROUND: The current economic constraints cause hospital management to use the available public resources as rationally as possible. At the same time, there is the necessity to improve current scientific knowledge. This is even more relevant in the case of patients with malignant pleural mesothelioma (MPM), given the severity of the disease, its dismal prognosis, and the cost of chemotherapy drugs. This work aims to evaluate the standard cost of patients with MPM, supporting physicians in their decision-making process in relation to budget constraints, as well as policy-makers with respect research policy. METHODS: The authors conducted a retrospective cost analysis on all the patients with MPM who were first admitted to a reference hospital specialized in MPM care between 2014 and 2015, collecting data on their diagnostic pathways and active treatments, as well as on the related official fees for each procedure. Then, using a multiple regression model, we estimated the overall expected cost of a patient with MPM treated in our hospital, to be born by the Regional Healthcare System based on the chosen clinical pathway. RESULTS: According to results, the economic impact of caring for a patient with MPM is mostly related to the selected active treatments, with drug and hospitalization costs as main drivers. Our analysis suggests that the expected reimbursed fee to care for a patient with MPM is equal to 18 214.99, with chemotherapy and monitoring costs equal to 12 861.43 and hospitalization cost equal to 5353.55. This cost decreases to 320.18 in the case of enrollment in an experimental trial of first-line treatment. In the other cases (second-line or third-line trials), the expected cost borne by the healthcare system for treating patients grows exponentially ( 40,124.18 and 59 839.94, respectively). CONCLUSION: Experimental trials might be a solution to decrease the economic burden for the public healthcare system only in the case of first-line treatments, where the cost of chemotherapy is relevant. Nevertheless, policy-makers have to accept the sharing of this economic burden between society and the pharmaceutical industry to broaden the current scientific knowledge.