Biomarker For Mesothelioma Research Articles

Strengths, Weaknesses, and Opportunities of Diagnostic Breathomics in Pleural Mesothelioma—A Hypothesis

Past and present asbestos use will reflect in increasing numbers of mesothelioma cases in the next decades, diagnosed at a late stage and with a dismal prognosis. This stresses the need for early detection tools, which could improve patients' survival. Recently, breath analysis as a noninvasive and fast diagnostic tool has found its way into biomedical research. High-throughput breathomics uses spectrometric, chromatographic, and sensor techniques to diagnose asbestos-related pulmonary diseases based upon volatile organic compounds (VOC) in breath. This article reviews the state-of-the-art available breath analyzing techniques and provides the insight in the current use of VOCs as early diagnostic or prognostic biomarkers of mesothelioma to stimulate further research in this field. Cancer Epidemiol Biomarkers Prev; 23(6); 898-908. ©2014 AACR.

Proteome Screening of Pleural Effusions Identifies Galectin 1 as a Diagnostic Biomarker and Highlights Several Prognostic Biomarkers for Malignant Mesothelioma

Malignant mesothelioma is an aggressive asbestos-induced cancer, and affected patients have a median survival of approximately one year after diagnosis. It is often difficult to reach a conclusive diagnosis, and ancillary measurements of soluble biomarkers could increase diagnostic accuracy. Unfortunately, few soluble mesothelioma biomarkers are suitable for clinical application. Here we screened the effusion proteomes of mesothelioma and lung adenocarcinoma patients to identify novel soluble mesothelioma biomarkers. We performed quantitative mass-spectrometry-based proteomics using isobaric tags for quantification and used narrow-range immobilized pH gradient/high-resolution isoelectric focusing (pH 4–4.25) prior to analysis by means of nano liquid chromatography coupled to MS/MS. More than 1,300 proteins were identified in pleural effusions from patients with malignant mesothelioma (n = 6), lung adenocarcinoma (n = 6), or benign mesotheliosis (n = 7). Data are available via ProteomeXchange with identifier PXD000531. The identified proteins included a set of known mesothelioma markers and proteins that regulate hallmarks of cancer such as invasion, angiogenesis, and immune evasion, plus several new candidate proteins. Seven candidates (aldo-keto reductase 1B10, apolipoprotein C-I, galectin 1, myosin-VIIb, superoxide dismutase 2, tenascin C, and thrombospondin 1) were validated by enzyme-linked immunosorbent assays in a larger group of patients with mesothelioma (n = 37) or metastatic carcinomas (n = 25) and in effusions from patients with benign, reactive conditions (n = 16). Galectin 1 was identified as overexpressed in effusions from lung adenocarcinoma relative to mesothelioma and was validated as an excellent predictor for metastatic carcinomas against malignant mesothelioma. Galectin 1, aldo-keto reductase 1B10, and apolipoprotein C-I were all identified as potential prognostic biomarkers for malignant mesothelioma. This analysis of the effusion proteome furthers our understanding of malignant mesothelioma, identified galectin 1 as a potential diagnostic biomarker, and highlighted several possible prognostic biomarkers of this disease.

The continual search for ideal biomarkers for mesothelioma: the hurdles.

Malignant pleural mesothelioma (MPM) is an aggressive tumour predominately caused by exposure to asbestos. Asbestos consumption continues to increase worldwide, particularly among developing nations in Asia. Although actual data on mesothelioma incident rates are unavailable from several of the world’s largest asbestos consuming nations including Russia, China and India (1), rates are predicted to surge in Asia reflecting the increased use of asbestos (2). Presently one person dies every four hours from mesothelioma in the United Kingdom.

Comparison of the Diagnostic Accuracy of theMSLNGene Products, Mesothelin and Megakaryocyte Potentiating Factor, as Biomarkers for Mesothelioma in Pleural Effusions and Serum

The MSLN gene products, soluble mesothelin and megakaryocyte potentiating factor (MPF), are being investigated as biomarkers for the asbestos-related cancer malignant mesothelioma (MM). Pleural fluid biomarkers of MM can be elevated when serum levels remain normal. The aim of this study was to determine if this was true for MPF and to compare levels of mesothelin. Biomarker concentrations were compared in 66 MM patients, 39 patients with other malignancies, 37 with benign disease, 18 asbestos-exposed healthy individuals, and 53 patients with chronic kidney disease. In pleural effusions, MPF and soluble mesothelin concentrations were both significantly elevated in MM patients relative to controls. No significant difference between the area under the receiver operator curve (AUC) for MPF (0.945 ± 0.02) and mesothelin (0.928 ± 0.03) when distinguishing MM from all other causes of effusion was observed. MPF and mesothelin serum concentrations were highly correlated and of equivalent diagnostic accuracy with AUCs of 0.813 ± 0.04 and 0.829 ± 0.03, respectively. Serum levels of both markers increased with decreasing kidney function. In conclusion, MPF is elevated in the pleural effusions of MM patients similar to that of mesothelin. Mesothelin and MPF convey equivalent diagnostic information for distinguishing MM from other diseases in pleural effusions as well as serum.

A key role of microRNAs as early biomarkers in mesothelioma

Mesothelioma is a rare cancer that is caused almost exclusively by exposure to asbestos. Although the use of asbestos has been reduced dramatically in recent decades, the incidence of mesothelioma has remained steady. Scientific literature has consistently shown that this disease has a latency period ranging between 20 and 60 years, then it will continue to rank among major social and healthcare issues for decades to come. There is no single established path to a mesothelioma diagnosis. However, the process often involves multiple procedures. The lack of biomarkers capable of providing predictive estimates for malignant pleural mesothelioma in relation to asbestos exposure in work and environment settings is a significant shortfall. The latter shortfall is compounded by a present-day lack of clinical or therapeutic options capable of stalling the development of pathology; hence the mean survival rate (from time of diagnosis) of approximately 10 months. This study provides a review of current knowledge on etiopathogenetic mechanisms in mesothelioma, and on diagnostic/prognostic biomarkers. As reported by recent literature, studies on microRNAs have proved to be of special interest. Main focus is addressed in particular at current knowledge progresses concerning the role of microRNAs in malignant pleural mesothelioma, showing the significance and uses of such biomarkers. A comparative analysis of different data from various reported papers reveals the consistency or the divergence of these results providing useful clues to suggest new directions in future research studies.

Fibulin-3 as a biomarker for mesothelioma

Fibulin-3 as a biomarker for mesothelioma

The Effect of Clinical Covariates on the Diagnostic and Prognostic Value of Soluble Mesothelin and Megakaryocyte Potentiating Factor

Soluble mesothelin (SM) and megakaryocyte potentiating factor (MPF) are serum biomarkers of mesothelioma. This study examined the effect of clinical covariates on biomarkers levels and their diagnostic and prognostic value. Five hundred ninety-four participants were enrolled in a multicenter study, including 106 patients with mesothelioma and 488 control subjects. Multiple linear regression analyses were used to identify which covariates were independently associated with SM and MPF levels. The effect of these covariates on the diagnostic accuracy was evaluated with receiver operating characteristics curve analysis. In patients with mesothelioma, survival analysis was performed with Cox regression. SM and MPF levels were independently associated with age, glomerular filtration rate (GFR), and BMI in control subjects and with GFR and tumor stage in patients with mesothelioma. The diagnostic accuracy of SM and MPF was significantly affected by the distribution of these covariates in the study population. The patients with mesothelioma were best discriminated from the control subjects with either the youngest age, the highest GFR, or the largest BMI. Furthermore, the control subjects were significantly better differentiated from stage II to IV than from stage I mesothelioma. MPF, not SM, was an independent negative prognostic factor, but only if adjusted for the biomarker-associated covariates. SM and MPF levels were affected by the same clinical covariates, which also had a significant impact on their diagnostic and prognostic value. To improve the interpretation of biomarker results, age, GFR, and BMI should be routinely recorded. Approaches to account for these covariates require further validation, as does the prognostic value of SM and MPF.

Soluble Mesothelin, Megakaryocyte Potentiating Factor, and Osteopontin as Markers of Patient Response and Outcome in Mesothelioma

Soluble mesothelin (SM), megakaryocyte potentiating factor (MPF), and osteopontin (OPN) are blood biomarkers of mesothelioma. This study evaluates their use as markers of response to therapy and outcome. Sixty-two patients with malignant pleural mesothelioma were included in an observational multicenter study. Blood samples and matched computed tomography scans were collected at diagnosis and, when possible, during and after therapy. For each patient, the best overall radiological response was compared with the changes in serum SM, MPF, and plasma OPN levels across corresponding time points. In five patients, blood sampling was done shortly before and after extrapleural pneumonectomy. SM and MPF levels markedly decreased after surgery, whereas OPN levels showed a median increase. Fifty-seven patients were surveilled during (and after) chemotherapy, of whom 27 (47%) had stable disease, 14 (25%) partial response, and 16 (28%) progressive disease. In patients with stable disease, SM and MPF levels did not change significantly across the corresponding time points, whereas OPN levels significantly decreased. In those with partial response, SM and MPF levels significantly decreased, whereas OPN levels showed no significant change. In patients with progressive disease, all three biomarker levels significantly increased. Patient responses correlated with a 15% change in all three biomarkers, although SM and MPF appeared more accurate than OPN. Low baseline OPN levels were independently associated with favorable progression-free survival and overall survival. Neither SM nor MPF showed prognostic value. SM and MPF levels were more closely associated with disease course than OPN and might prove useful in monitoring patient response in mesothelioma. Baseline OPN levels were an independent negative predictor of survival. These promising results require further validation.

Lung cancer a hot topic at AACR meeting

Lung cancer a hot topic at AACR meeting

Soluble mesothelin, megakaryocyte potentiating factor, and osteopontin as markers of patient response and outcome in malignant pleural mesothelioma.

7086 Background: Radiological response evaluation is notoriously difficult in patients with malignant pleural mesothelioma, an asbestos-related malignancy. Soluble mesothelin (SM), megakaryocyte potentiating factor (MPF), and osteopontin (OPN) are blood biomarkers of mesothelioma. This study evaluates their use as markers of response to therapy and outcome. Methods: 62 patients with malignant pleural mesothelioma were surveilled in a Belgian observational multicenter study. Blood samples and CTs were collected at diagnosis and, when possible, during and after therapy, until disease progression or death. SM and MPF levels were measured in serum with the Mesomark ELISA and the non-commercial Human MPF ELISA, respectively. OPN levels were measured in plasma with the Human Osteopontin ELISA. For each patient, the best overall radiological response was compared with the change in serum SM, MPF and plasma OPN levels across the corresponding time points. Survival analysis was performed with Cox proportional hazard regression and log-rank statistics. Results: In five patients who underwent extrapleural pneumonectomy, SM and MPF markedly decreased after surgery, whereas OPN showed a median increase. Of the 57 patients who received chemotherapy, 27 (47%) had radiological stable disease (SD), 14 (25%) partial response (PR), and 16 (28%) progressive disease (PD). In patients with SD, biomarker levels did not change significantly (SM and MPF), or decreased (OPN). For PR and PD, biomarker levels typically decreased and increased, respectively. A change ≥15% in all three biomarkers significantly correlated with patient response, whereas SM and MPF appeared more accurate than OPN. Low baseline OPN levels were independently associated with favorable overall and progression free survival. Neither SM nor MPF were informative for patient outcome. Conclusions: Relative changes in SM, MPF and OPN all three correlated with disease course, whereas SM and MPF appeared most suitable for monitoring of patients with mesothelioma. Baseline OPN levels were an independent negative predictor of survival. Further validation of these promising results remains mandatory.

Serial Measurements of Mesothelioma Serum Biomarkers in Asbestos-Exposed Individuals: A Prospective Longitudinal Cohort Study

Soluble mesothelin (SM) and megakaryocyte potentiating factor (MPF) are serum biomarkers of mesothelioma. This study aims to examine the longitudinal behavior of SM and MPF in controls to gain insight in the optimal use of these biomarkers in screening. Asbestos-exposed individuals, with no malignant disease at inclusion, were surveilled for 2 years with annual measurements of SM and MPF. Fixed thresholds were set at 2.10 nmol/L for SM and 13.10 ng/ml for MPF. Longitudinal biomarker analysis, using a random intercept model, estimated the association with age and glomerular filtration rate (GFR), and the intraclass correlation. The latter represents the proportion of total biomarker variance accounted for by the between-individual variance. A total of 215 participants were included, of whom 179 and 137 provided a second sample and third sample, respectively. Two participants with normal SM and MPF levels presented afterward with mesothelioma and lung cancer, respectively. Participants with elevated biomarker levels were typically older and had a lower GFR. During follow-up, biomarker levels significantly increased. Longitudinal analysis indicated that this was in part due to aging, while changes in GFR had a less pronounced effect on serial biomarker measurements. SM and MPF had a high intraclass correlation of 0.81 and 0.78, respectively, which implies that a single biomarker measurement and fixed threshold are suboptimal in screening. The longitudinal behavior of SM and MPF in controls indicates that a biomarker-based screening approach can benefit from the incorporation of serial measurements and individual-specific screening rules, adjusted for age and GFR. Large-scale validation remains nevertheless mandatory to elucidate whether such an approach can improve the early detection of mesothelioma.

Serum Mesothelin for Early Detection of Asbestos-Induced Cancer Malignant Mesothelioma

Malignant mesothelioma is an aggressive, almost uniformly fatal tumor, primarily caused by exposure to asbestos. Since the recent discovery that serum mesothelin is a sensitive and highly specific biomarker for mesothelioma, one of the key issues raised is whether mesothelin levels represent a useful screening test for asbestos-exposed at-risk individuals. In this study, soluble mesothelin was determined in sequential serum samples collected from asbestos-exposed individuals before the development of mesothelioma. Archival serum samples from 106 individuals who developed mesothelioma, 99 asbestos-exposed individuals from the Wittenoom Cancer Surveillance Program, and 109 non-asbestos-exposed individuals from the Busselton Health Survey were identified. Serum mesothelin concentrations were determined using the MESOMARK assay. Longitudinal mesothelin levels determined in healthy asbestos-exposed individuals over a period of 4 years were stable (Pearson's r = 0.96; P < 0.0001). There was no correlation between mesothelin concentration and cumulative asbestos exposure. Mesothelin concentrations were greater than the threshold value of 2.5 nmol/L in the penultimate serum sample before the diagnosis of mesothelioma in 17 of 106 people. Using an increase above the 95% confidence interval of the mean of a given individual's longitudinal mesothelin results, 33 of 82 individuals had increasing mesothelin levels before diagnosis. In a population with a high pretest probability of developing mesothelioma, the serum biomarker mesothelin is elevated in absolute terms in 15% and in relative terms in 40% of the group. Future studies examining a combination of biomarkers could improve sensitivity of screening.

Abstract 4053: One MicroRNA Has Prognostic Potential For Malignant Pleural Mesothelioma

Abstract Introduction: The current inability to forecast outcomes for malignant pleural mesothelioma prevents clinicians from providing aggressive multimodality therapy to the most appropriate individuals who may benefit from such an approach, and hence compromises their prognosis. It was previously shown that microRNAs (miRs) have a role in the cancer process, and that they can serve as biomarkers for different tumors or histological types. Here we investigated whether specific miRs could differentiate a largely surgically-treated group of mesotheliomas into good or bad prognosis categories. Methods: In a retrospective study using snap frozen, immunohistochemically-proven mesothelioma surgical specimens, we looked for miRs associated with survival and time to progression. A training set of 44 and a test set of 98 mesothelioma tumor samples were analyzed by a custom ∼900 microRNA microarray platform and verified by qRT-PCR for cross-platform validation. Patients were segregated into good or bad time to progression (greater/less than 12 months) and into good or bad survival (greater/less than 15 months). Mann-Whitney tests for good vs. bad prognosis and Kaplan-Meier analysis were used to detect prognosticator miRs. The biological effect of the identified prognostic miR was tested in 2 mesothelioma cell lines. Functional implications as well as downstream targets of the potential prognostic miR were investigated in vitro. Results: In both the training and test sets, one miR was an independent prognostic factor for time to progression as well as survival after surgical cytoreduction. The miR was expressed at higher levels in epithelial mesothelioma than in sarcomatoid cases, and the level of this miR could segregate patients with this histology into groups with differing prognosis. Thresholds set within the training set for microarray reading were fully valid in the test-set, as was the comparable threshold using qRT-PCR. Increased expression of this specific miR predicted throughout a more favorable prognosis, and overexpression of the miR in mesothelioma cell lines resulted in significantly decreased proliferation, migration, invasion, and colony formation. Moreover, major epigenetic regulatory genes, known in mesothelioma, are mediated by this miR as was demonstrated through downregulation of DNA methyltransferases as well as upregulation of demethylating genes. This suggests that a control mechanism might explain the clinical findings, supporting their validity. Conclusions: One miR has the potential to be a prognostic biomarker in mesothelioma and shows the ability to change proliferation, migration, invasion upon over-expression in mesothelioma cell lines. Further validation of these findings as well as investigation of its downstream targets may give insight for potential therapies in the future, by allowing personalized treatment for patients who are more to benefit. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4053.

Hsa-miR-29c* Is Linked to the Prognosis of Malignant Pleural Mesothelioma

The inability to forecast outcomes for malignant mesothelioma prevents clinicians from providing aggressive multimodality therapy to the most appropriate individuals who may benefit from such an approach. We investigated whether specific microRNAs (miR) could segregate a largely surgically treated group of mesotheliomas into good or bad prognosis categories. A training set of 44 and a test set of 98 mesothelioma tumors were analyzed by a custom miR platform, along with 9 mesothelioma cell lines and 3 normal mesothelial lines. Functional implications as well as downstream targets of potential prognostic miRs were investigated. In both the training and test sets, hsa-miR-29c* was an independent prognostic factor for time to progression as well as survival after surgical cytoreduction. The miR was expressed at higher levels in epithelial mesothelioma, and the level of this miR could segregate patients with this histology into groups with differing prognosis. Increased expression of hsa-miR-29c* predicted a more favorable prognosis, and overexpression of the miR in mesothelioma cell lines resulted in significantly decreased proliferation, migration, invasion, and colony formation. Moreover, major epigenetic regulation of mesothelioma is mediated by hsa-miR-29c* and was shown through downregulation of DNA methyltransferases as well as upregulation of demethylating genes. A single miR has the potential to be a prognostic biomarker in mesothelioma, and validation of these findings as well as investigation of its downstream targets may give insight for potential therapies in the future.

OP82 Diagnostic performance of soluble mesothelin and megakaryocyte potentiating factor as biomarkers of mesothelioma

The Eker rat develops hereditary renal carcinomas (RCs) due to two hit mutations of the tumor suppressor gene, Tsc2. We previously identified using representational difference analysis (RDA), four genes that were expressed more abundantly in an Eker rat RC cell line than in normal kidney tissue. One gene, Erc (expressed in renal carcinoma) showed sequence homology to the mouse and human megakaryocyte potentiating factor (MPF)/mesothelin gene. The present study determines the full sequence of the cDNA and the exon–intron structure of the rat Erc gene and maps its locus in the chromosome by fluorescence in situ hybridization. Rat Erc and its human homologue were localized in chromosomes 10q12–21 and 16p13.3, respectively, both of which coincided with the locus of the Tsc2/TSC gene. We also found that Erc was expressed at higher levels in primary RCs compared with the normal kidney of the Eker rat. Erc may be related to carcinogenesis in the Tsc2 gene mutant (Eker) rat model.

Serum and pleural fluid biomarkers for mesothelioma

Malignant mesothelioma is an asbestos-induced, aggressive tumour. In centres across the world, research has focused on evaluating biomarkers for malignant mesothelioma screening, diagnosis, prognostication and monitoring. With the incidence of malignant mesothelioma expected to increase, it is timely to review the current status of biomarkers in this field. The majority of recent studies have evaluated the commercial MESOMARK assay in a diagnostic setting. Studies have clarified that soluble-shed mesothelin as well as mesothelin-related peptide are targets of the assay. The assay sensitivity ranges from 50% at diagnosis to 84% in advanced disease. The assay has a high level of specificity relative to benign lung and pleural conditions and is positive in 10-15% of other malignancies. In a prospective screen of 538 asbestos-exposed workers, 2.8% were positive; one had lung cancer that was subsequently successfully treated. The biomarkers megakaryocyte potentiating factor, osteopontin and CA125, either alone or in combination with soluble mesothelin, have also been assessed. To date, soluble mesothelin remains the best available biomarker for malignant mesothelioma. However, a lack of sensitivity for early-stage disease and for all malignant mesothelioma histologies provides motivation for the search of novel malignant mesothelioma biomarkers with greater sensitivity, especially for very early disease.

Sensitive and Specific New Enzyme-Linked Immunosorbent Assay for N-ERC/Mesothelin Increases its Potential as a Useful Serum Tumor Marker for Mesothelioma

Because mesothelioma initially progresses on the surface of the pleura and peritoneum without forming masses, it has been difficult to diagnose at an early stage. It would be very useful to identify a tumor marker that could be used for screening to enable more diagnoses to be made at an early, treatable stage. We had previously identified N-ERC/mesothelin as a potential biomarker for mesothelioma. In the current work, we used a newly developed ELISA system to gain data on N-ERC/mesothelin levels in various clinical settings. A total of 102 healthy volunteers were recruited. In addition, 39 patients were diagnosed with mesothelioma, 53 patients were diagnosed with diseases that should be distinguished from mesothelioma, and 201 subjects were diagnosed with asbestos-related nonmalignant diseases (including simple exposure to asbestosis) who were treated at any of the cooperating hospitals were enrolled. Serum N-ERC/mesothelin levels measured by a new ELISA system showed that the median values from patients with mesothelioma were extremely high compared with levels obtained from other patients. Analysis in terms of histologic type showed that serum levels of N-ERC/mesothelin were elevated in epithelioid type mesothelioma, especially. In four important models of clinical settings, the sensitivity and specificity of N-ERC/mesothelin were about 71% to 90% and 88% to 93%, respectively. N-ERC/mesothelin is a very promising tumor marker for mesothelioma, especially epithelioid mesothelioma.

151 Discovery and validation of novel serological biomarkers of mesothelioma

151 Discovery and validation of novel serological biomarkers of mesothelioma