Soluble Mesothelin-related Peptide Research Articles

Clinical value of mesothelin in pleural effusions versus histology by medical thoracoscopy: brief report

The aim of this study based on the third phase of the architecture of diagnostic research was to assess the sensitivity and specificity of soluble mesothelin-related peptide (SMRP) in pleural exudative effusions (PE) compared to the histology obtained by medical thoracoscopy as the diagnostic gold standard examination. We assessed 104 consecutive thoracoscopies. SMRP concentrations were obtained using an ELISA test. We had 34 mesotheliomas (25 epithelioid and 9 sarcomatoid), 35 pleural metastases, and 35 benign diseases. PE-SMRP were significantly higher in patients with epitheliomorphic mesothelioma (mean ± SD 46.55 ± 44.29 nM) than in patients with sarcomatoid mesothelioma (16.11 ± 25.02 nM; p = 0.061), pleural metastasis (7.52 ± 10.77 nM; p < 0.0001), or benign diseases (5.82 ± 8.86 nM; p < 0.0001). Using ROC curve analysis, PE-SMRP offered an AUC of 0.767 in its ability to differentiate between patients with mesothelioma and all other diagnoses. The diagnostic sensitivity and specificity of PE-SMRP for distinguishing mesothelioma from all other causes of pleural effusion, at a cut-off value of 19.6 nM, were 58.8 and 97.1 %, respectively. PE-SMRP higher than the assumed cut-off of 19.6 nM were observed in 18/25 (72.0%) epitheliomorphic mesotheliomas, 2/9 (22.2%) sarcomatoid mesotheliomas, 5/35 (14.3%) pleural metastases, and 1/35 (2.9%) benign diseases. We conclude that PE-SMRP adds some clinical information in the work-up of patients with a PE of unknown origin: (1) thoracoscopy should always be done in patients with a positive mesothelin; (2) a negative mesothelin does not exclude a malignant disease.

Combination of Mesothelin and CEA Significantly Improves the Differentiation between Malignant Pleural Mesothelioma, Benign Asbestos Disease, and Lung Cancer

Soluble mesothelin-related peptides (SMRP) have been reported as potential markers for the diagnosis of malignant pleural mesothelioma (MPM). We wondered, whether a combination with a carcinoembryonic antigen (CEA) test might improve the relatively low diagnostic yield of the SMRP test. In a retrospective study, SMRP (mesothelin) and CEA serum concentrations were measured, using commercially available kits, in 93 previously untreated MPM patients, 75 patients with benign asbestos disease, and 139 patients suffering from lung cancer (LC). The differentiation between MPM, LC, and benign asbestos disease could be improved by applying the ratio mesothelin/CEA. Whereas CEA expression was found to be low in MPM, most LC patients had elevated CEA serum levels. The area under curve (AUC) of the receiver operator characteristics curve for mesothelin alone was found to be only 0.708. For mesothelin/CEA the AUC of the receiver operator characteristics curve increased to 0.978. The sensitivity was 93% (69%) at 95% (100%) specificity for the differentiation between MPM and LC. Comparison of MPM and benign asbestos disease showed that the AUC was 0.887 and the sensitivity 56% (47%) at 95% (100%) specificity. In contrast, the AUC for the mesothelin test alone was only 0.715, and for the CEA test alone it was 0.16. An average increment in sensitivity of 38% (range, 16%-63%) could be achieved by the quotient mesothelin/CEA compared with the sensitivity of mesothelin alone. The diagnostic yield of the mesothelin test can be considerably improved when combined with a CEA test with regard to the differential diagnosis between MPM and LC and between MPM and benign asbestos disease.

SMRP in screening of mesothelioma in asbestos-exposed workers: A study of 1,704 subjects.

e12518 Background: The soluble mesothelin-related peptide (SMRP) is a marker in the diagnosis for mesothelioma. The role of SMRP as a potential screening tool in subjects with a past asbestos exposure is being debated. Objective: to evaluate SMRP and incidence of malignant mesothelioma in an asbestos exposed cohort. Methods: 1,704 subjects (Median Age 62) occupationally exposed to asbestos were enrolled in the study. A questionnaire on individual characteristics, disease history, and occupational or non-occupational exposure to asbestos was administered. All subjectsunderwent clinical examination and collection of serum sample for SMRP measurement that were repeated after 1 and 2 years. The samples were stored at -80 °C until assayed. Results: Median baseline SMRP was 0.45 nmol/l (range 0.1-4.45). SMRP was higher than 1.5 nmol/l (defined as cut-off) in 40 participants. 9 subjects had recognized lung cancer at the time of screening (median baseline SMRP 0.65 nmo/l, range 0.1-1.7) and 109 had recognized tumors at other sites (median 0.52 nmol/l, range 0.1-3.0). Overall, median follow-up of all subjects was 31.5 months During follow-up, recurrent or metastatic tumors were observed in 23 out of 118 tumors. Sixty-one subjects developed a new tumor. An epithelioid pleural mesothelioma occurred in two subjects, 13 and 17 months after the last SMRP evaluation, respectively. Baseline SMRP was 0.52 nmol/l and 0.17 nmol/l, respectively. In subjects with tumor, SMRP increased of 20-50% in 13 subjects (15%), two of them with abnormal SMRP (1 bladder and 1 prostate cancer). An increase greater than 50% was found in 19 subjects (22%). SMRP was higher than the threshold value in 3 tumors (1 lung, 1 colon and 1 prostate, diagnosed 2 months from last SMRP measure). Overall, mesothelin was above the cut-off in 58 subjects without any evidence of neoplastic disease. Conclusions: we cannot confirm the predictive role of SMRP for mesothelioma because we found two cases with low mesothelin levels 13 and 17 months before the diagnosis. The low number of mesotheliomas could be due to the low median age of our population. It will be intriguing to follow up in the future the subjects that showed an increase of SMRP.

Diagnostic value of mesothelin in pleural fluids: comparison with CYFRA 21-1 and CEA

CYFRA 21-1 and CEA have been applied for the differential diagnosis of malignant pleural mesothelioma (MPM). The soluble mesothelin-related peptide (SMRP) has been proposed as a specific marker for distinguishing MPM from benign diseases and other malignancies in pleural effusions (PEs). In this study, we evaluated the usefulness of SMRP in PEs in the detection of mesotheliomas by comparing it with that of CYFRA 21-1, CEA, and with cytological examination. One hundred and seventy-seven consecutive patients (57 MPM, 64 metastatic tumors, and 56 benign diseases) were evaluated using commercial tests. The performance of the markers was analyzed by standard ROC analysis methods, using the area under a ROC curve (AUC) as a measure of accuracy. CYFRA 21-1 better differentiated malignant from benign effusions. The corresponding area under the receiver operating characteristic curve was 0.87, while it was 0.74 for SMRP and 0.64 for CEA (p < 0.001). Conversely, SMRP differentiated MPM from all other PEs better than both CYFRA 21-1 and CEA (AUC = 0.84, 0.76, and 0.32, respectively, p = 0.003). Low levels of CEA were associated with a MPM diagnosis. The AUC for differentiating MPM from metastases was 0.81 for SMRP, 0.61 for CYFRA 21-1, and 0.20 for CEA (p < 0.001). In cases with negative or suspicious cytology, SMRP and CYFRA 21-1 identified 36/71 and 46/66 malignant PEs (29 and 31 MPM, respectively). Only 1 MPM showed a high CEA concentration. No single marker showed the best performance in any comparison. Results suggest that SMRP could improve CYFRA 21-1 and CEA accuracy in the differential diagnosis of MPM.

Individual predictors of increased serum mesothelin in asbestos-exposed workers

The soluble mesothelin-related peptide (SMRP), a candidate marker for screening of subjects with asbestos exposure, is influenced by some individual and clinical factors. The aim of this study was to quantify the role of age, smoking, weight, presence of diseases and exposure to asbestos on serum SMRP levels in a large series of subjects exposed to asbestos, possible candidates for mesothelioma screening. One thousand seven hundred and four participants underwent clinical examination and were interviewed on medical anamnesis, occupation, smoking and weight. SMRP was measured by an ELISA assay. Overall, median SMRP was 0.4 (IQR 25-75: 0.3-0.7) nmol/l. It was higher in current smokers and in subjects with a cumulative asbestos exposure >50 ff/cc/years than in all the other subjects (p < 0.001 and p = 0.002, respectively). SMRP was positively correlated with age (ρ = 0.11, p < 0.001) and, inversely, with BMI (ρ = -0.15, p < 0.001). SMRP was lower in healthy subjects (n = 1,217: median 0.4 nmol/l) than in subjects with malignant tumors (n = 118: 0.5 nmol/l; p = 0.01), asbestos-related pleural lesions (plaques or thickenings, n = 152: 0.6 nmol/l; p < 0.001) and other benign diseases (n = 182: 0.5 nmol/l; p = 0.04). Multivariate analysis revealed significant predictors of increased SMRP: age >57 years, current smoking, a positive anamnesis for cancer and for asbestos-related pleural lesions, and BMI < 25. Some clinical and demographic variables are associated with serum SMRP levels. The degree of these associations is low, nevertheless they should be accounted for in the interpretation of SMPR as a candidate marker predictive of mesothelioma. The potential predictive value of serum SMRP in screening/surveillance programs must be validated in prospective studies.

Cancer antigen 125, human epididymis 4, kallikrein 6, osteopontin and soluble mesothelin-related peptide immunocomplexed with immunoglobulin M in epithelial ovarian cancer diagnosis

Human epididymis protein 4 (HE4), kallikrein 6 (KLK6), osteopontin (OPN) and soluble mesothelin-related peptide (SMRP) are new promising biomarkers that could integrate CA125 in epithelial ovarian cancer (EOC) diagnosis. The autoantibody response to tumor antigens is a potential tool for improving the diagnostic performances of biomarkers. The aim of this study was to assess the diagnostic potential of these biomarkers in the form of free markers and immunocomplexed with immunoglobulin M (IgM). Moreover, we analyzed the association between these markers and clinico-pathological characteristics of EOC patients. Serum and plasma samples of 60 healthy controls, 60 ovarian benign cysts, 60 endometriosis and 60 EOCs, collected before any treatment, were tested for CICs and free antigens by immunoassays. Immunocomplexes were characterized by poor sensitivity and specificity, since they allowed the detection only of a small number of EOC patients and were increased in patients with benign gynecological pathologies. However, the markers in the form of free antigens showed good diagnostic performances. Of note, CA125 and HE4 showed high sensitivity in the detection of the malignancy and HE4 emerged as a useful biomarker in differential diagnosis between EOC and endometriosis. Finally, elevated KLK6 and OPN, were associated with advanced FIGO stage, high grade disease, suboptimally debulked tumor and ascites. This study confirms the diagnostic role of CA125, HE4, KLK6, OPN and SMRP, and for the first time showed that CA125, HE4, KLK6, OPN and SMRP immunocomplexed with IgM are not a potential tool for EOC diagnosis.

Evaluation of Soluble Mesothelin-related Peptide as a Diagnostic Marker of Malignant Pleural Mesothelioma Effusions: Its Contribution to Cytology

Soluble mesothelin-related peptide (SMRP) is regarded as an FDA approved biomarker for the diagnosis and monitoring of pleural malignant mesothelioma (MPM). We detected the SMRP levels in pleural effusions (PE) by means of an ELISA and analyzed their diagnostic relevance to differentiate MPM from benign pathology and from non-MPM pleural metastasis. Comparison with cytology in MPM-PE was also performed. We found that SMRP detection in MPM-PE can help the diagnosis of MPM and provide additional diagnostic value to cytology. We concluded that SMRP test may be incorporated into clinical practice of PE from patients suspicious for MPM.

Mesothelioma

Mesothelioma

Soluble Mesothelin-Related Peptide in the Pleural Fluid as a Diagnostic Marker in Malignant Pleural Mesothelioma

Soluble Mesothelin-Related Peptide in the Pleural Fluid as a Diagnostic Marker in Malignant Pleural Mesothelioma

192P - Mesothelin and Individual Characteristics in a Cohort of Asbestos Exposed Workers

ABSTRACT Headings The soluble mesothelin-related peptide (SMRP) is a candidate marker in the diagnosis and prognosis of mesothelioma, as well as in the screening of subjects with asbestos exposure. SMRP seems to be influenced by some individual characteristics and clinical factors. Objective The objective of this study was to evaluate the association between serum SMRP and some individual characteristics in 1704 subjects exposed to asbestos for working reasons. Design and methods Participants underwent clinical examination and were interviewed on medical history, occupational exposure, smoking and weight. SMRP was measured by a ELISA assay. Results Median SMRP was 0.45 (IQR 0.30-0.67) nmol/l. SMRP was correlated with age (p Conclusions Data on a large series of subjects with asbestos exposure confirmed that serum SMRP is associated to a number of clinical and demographic variables. Disclosure All authors have declared no conflicts of interest.

Evaluation of soluble mesothelin-related peptide as a marker additional to cytology for diagnosing malignant pleural mesothelioma effusions.

e17533 Background: Detection of soluble mesothelin-related peptide (SMRP) levels in serum has been proposed to help the diagnosis of malignant pleural mesothelioma (MPM). In this study we evaluated the SMRP levels in pleural effusions of MPM (MPM-PE), the clinical importance and usefulness of SMRP detection in MPM-PE and whether it can have an additional value to cytological analysis (Cyt). Methods: We studied 52 MPM-PE, 129 benign PE (B-PE) and 94 non-MPM pleural metastasis PE (Mts-PE). In all PE samples, both cytology and SMRP detection were performed. SMRP levels were estimated by means of the MesoMark ELISA kit (Fujirebio Diagnostic, Malvern, PA). Diagnostic performance parameters were estimated through the ROC analysis, Youden's index was applied to obtain the best cut-off level and the degree of correlation was estimated by Diagnostic Odds Ratio (DOR) and by P-value (P) with Chi-square test. Results: The median SMRP levels were significantly higher in MPM-PE (28.2 nM) than in B-PE (3.2 nM) or Mts-PE (3.8 nM). MPM-PE vs B-PE yielded an AUC of 84.5 (P&lt;0.001) whereas MPM-PE vs Mts-PE yelded an AUC of 79.6 (P&lt;0.001). The cut off level in MPM-PE was estimated in 9.30 nM at which value we established Se=75%, Sp=93% for MPM-PE vs BPE and SP=81% for MPM-PE vs Mts-PE. We found SMRP positive cases (≥ cut off) in 38/52 (73%) MPM-PE, in 9/129 (7%) B-PE (DOR=40, P&lt;0.001) and in 18/94 (19%) Mts-PE (DOR=13, P&lt; 0.001).Cyt was negative in 29/52 (56%) of MPM-PE, among which SMRP was positive in 20/29 (69%) cases. Cyt was positive in 15/52 (29%) of MPM-PE, among which SMRP was negative in 4/15 (27%) cases. Finally, in 8/52 (15%) MPM-PE Cyt diagnosis was suspicious and SMRP was found positive in 7/8 (88%) cases. Conclusions: Our results demonstrate that SMRP levels in PE are significantly higher in MPM-PE than in PE from other pathologies. However the test cannot be alternative to cyt but it may provide additional diagnostic value to Cyt. SMRP detection in MPM-PE can be applied in the workup of patients with a PE of unknown origin.

CCL2, Galectin-3, and SMRP Combination Improves the Diagnosis of Mesothelioma in Pleural Effusions

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis. One major challenge for this disease is the development of new, early, and highly reliable diagnostic markers. The aim of this study was to compare the diagnostic value of the chemokine chemokine (C-C motif) ligand 2 (CCL2), galectin-3, and the secretory leukocyte peptidase inhibitor (SLPI) with soluble mesothelin-related peptides (SMRP), and to evaluate the diagnostic performance of marker combinations. The levels of the different markers were measured by enzyme-linked immunosorbent assay in pleural fluids from patients with MPM (n = 61), adenocarcinomas (ADCA, n = 25), or with benign pleural effusions (BPE, n = 15). SMRP, SLPI, and CCL2 concentrations were significantly higher in pleural effusions from mesothelioma patients. Conversely, galectin-3 levels seemed to be elevated in patients with pulmonary ADCA. Receiver operating characteristic curve analysis revealed that SMRP (area under the curve [AUC] = 0.9059), CCL2 (AUC = 0.7912), galectin-3 (AUC = 0.7584), and SLPI (AUC = 0.7219) were potentially interesting biomarkers for the differentiation of MPM patients from those with BPE or ADCA. Of interest, we showed that the combination of SMRP/CCL2/galectin-3 greatly improved MPM diagnosis (AUC = 0.9680), when compared with SMRP alone. The combination of SMRP/CCL2/galectin-3 seems to represent a promising panel of biomarkers for the reliable diagnosis of MPM in pleural fluids.

Tissue and Serum Mesothelin Are Potential Markers of Neoplastic Progression in Barrett's Associated Esophageal Adenocarcinoma

Mesothelin is overexpressed in several malignancies and is purportedly a specific marker of malignant transformation. In this pilot study, we investigated whether tissue and serum mesothelin are potential markers of neoplastic progression in Barrett's esophagus (BE) and in esophageal adenocarcinoma (EAC). Mesothelin expression was retrospectively evaluated in normal, BE, and EAC tissue from surgically resected esophageal specimens (n = 125). In addition, soluble mesothelin-related peptide (SMRP) levels were measured in serum. Normal esophageal mucosa did not express mesothelin. BE tissue with high-grade dysplasia specifically expressed mesothelin, whereas BE tissue with low-grade or without dysplasia did not. Fifty-seven (46%) EAC tumors were positive for mesothelin. EAC tumors with BE expressed mesothelin more often than those without BE (58% vs. 35%, P = 0.01). SMRP levels were elevated in 70% of EAC patients (mean = 0.89 nmol/L; range: 0.03-3.77 nmol/L), but not in patients with acid reflux and/or BE. Mesothelin is commonly expressed in BE-associated EAC. On the basis of this pilot study, a prospective study is under way to evaluate tissue and serum mesothelin which are potential markers of neoplastic progression in BE and in EAC (NCT01393483). Current surveillance methods in Barrett's esophagus are invasive and neither cost-effective nor sensitive. This pilot study suggests that serum mesothelin is a marker of neoplastic transformation in BE and may provide a noninvasive method to improve identification of malignant transformation.

Association of Biomarker Levels with Severity of Asbestos-Related Diseases

ObjectivesAsbestos-related diseases (ARDs) have increased globally over the decades, causing an economic burden and increased health care costs. It is difficult to predict the risk of development of ARDs and of respiratory disability among workers with a history of asbestos exposure. Blood based biomarkers have been reported as promising tools for the early detection of malignant mesothelioma. This study investigated whether serum soluble mesothelin-related peptide (SMRP) would reflect severity of disablement in compensable ARDs.MethodsSMRP levels were measured in a cohort of 514 asbestos-exposed subjects. Severity of ARDs was assessed by a Medical Authority comprising four specially qualified respiratory physicians. Severity of ARDs and SMRP levels were compared.ResultsMean (standard deviation) serum SMRP level in the population with compensable ARDs (n = 150) was 0.95 (0.65) nmol/L, and was positively associated with disability assessment (p = 0.01). Mean SMRP level in healthy asbestos-exposed subjects was significantly lower than those with pleural plaques (p < 0.0001) and in subjects with ARDs who received compensation (p < 0.01).ConclusionThis study indicates that serum SMRP levels correlate with severity of compensable ARDs. Serum SMRP could potentially be applied to monitor progress of ARDs. Further prospective work is needed to confirm the relationship between SMRP and disability assessment in this population.

Soluble mesothelin-related peptides levels in patients with malignant mesothelioma.

Soluble mesothelin-related peptides (SMRP) are a potential tumor marker for malignant mesothelioma. The aim of this study was to determine the differences in SMRP levels in patients with malignant mesothelioma before treatment and in various responses to treatment and to investigate whether SMRP level could be useful in evaluating tumor response to treatment. The study included patients with malignant mesothelioma treated at the Institute of Oncology Ljubljana between March 2007 and December 2009. Blood samples were collected before treatment and/or in various responses to treatment. SMRP levels were determined using ELISA assay based upon a combination of two monoclonal antibodies. Mann-Whitney test was used to determine the differences in SMRP levels in various responses to treatment.Median SMRP was 2.80 nmol/L (range 0.00–34.80) before treatment, 0.00 nmol/L (range 0.00–0.00) in complete response, 0.48 nmol/L (range 0.00–4.40) in partial response, 1.65 nmol/L (range 0.00–20.71) in stable disease and 7.15 nmol/L (range 0.44–31.56) in progressive disease. Pre-treatment SMRP levels were significantly higher than in stable disease, partial response and complete response (p=0.006), as were SMRP levels in progressive disease compared to stable disease, partial response and complete response (p = 0.006), as were SMRP levels in progressive disease compared to stable disease, partial response and complete response (p < 0.001).Our findings suggest that SMRP may be a useful tumor marker for detecting the progression of malignant mesothelioma and evaluating tumor response to treatment.

Soluble Mesothelin-Related Peptides Levels in Patients with Malignant Mesothelioma

Soluble mesothelin-related peptides (SMRP) are a potential tumor marker for malignant mesothelioma. The aim of this study was to determine the differences in SMRP levels in patients with malignant mesothelioma before treatment and in various responses to treatment and to investigate whether SMRP level could be useful in evaluating tumor response to treatment. The study included patients with malignant mesothelioma treated at the Institute of Oncology Ljubljana between March 2007 and December 2009. Blood samples were collected before treatment and/or in various responses to treatment. SMRP levels were determined using ELISA assay based upon a combination of two monoclonal antibodies. Mann-Whitney test was used to determine the differences in SMRP levels in various responses to treatment.Median SMRP was 2.80 nmol/L (range 0.00–34.80) before treatment, 0.00 nmol/L (range 0.00–0.00) in complete response, 0.48 nmol/L (range 0.00–4.40) in partial response, 1.65 nmol/L (range 0.00–20.71) in stable disease and 7.15 nmol/L (range 0.44–31.56) in progressive disease. Pre-treatment SMRP levels were significantly higher than in stable disease, partial response and complete response (p=0.006), as were SMRP levels in progressive disease compared to stable disease, partial response and complete response (p= 0.006), as were SMRP levels in progressive disease compared to stable disease, partial response and complete response (p&lt; 0.001).Our findings suggest that SMRP may be a useful tumor marker for detecting the progression of malignant mesothelioma and evaluating tumor response to treatment.

An In Vivo Platform for Tumor Biomarker Assessment

Tumor biomarkers provide a quantitative tool for following tumor progression and response to therapy. However, investigations of clinically useful tumor biomarkers are time-consuming, costly, and limited by patient and tumor heterogeneity. In addition, assessment of biomarkers as indicators of therapy response is confounded by the concomitant use of multiple therapeutic interventions. Herein we report our use of a clinically relevant orthotopic animal model of malignant pleural mesothelioma for investigating tumor biomarkers. Utilizing multi-modality imaging with correlative histopathology, we demonstrate the utility and accuracy of the mouse model in investigating tumor biomarkers – serum soluble mesothelin-related peptide (SMRP) and osteopontin (OPN). This model revealed percentage change in SMRP level to be an accurate biomarker of tumor progression and therapeutic response – a finding consistent with recent clinical studies. This in vivo platform demonstrates the advantages of a validated mouse model for the timely and cost-effective acceleration of human biomarker translational research.

Combined Serum Mesothelin and Plasma Osteopontin Measurements in Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a lethal tumor related to asbestos exposure. At present, the only instruments for screening and diagnosis are based on radiological tests, posing evident economic and radio-protectionist problems. Some authors are evaluating biological indicators, such as plasma osteopontin (pOPN) and serum soluble mesothelin-related peptides (SMRP). This study aimed to evaluate whether a combination of these two markers could increase sensitivity and specificity in diagnosis of epithelioid MPM. We enrolled 93 healthy subjects, 111 individuals with benign respiratory disease (BRD), and 31 patients with MPM, histologically and/or cytologically confirmed. SMRP and pOPN levels were determined using commercially available enzyme-linked immunosorbent assay kits. Though a logistic regression analysis, SMRP and pOPN were combined and translated into a new index, called "combined risk index." Differences in both SMRP and pOPN mean values between epithelial MPM patients and healthy subjects or BRD patients were statistically significant (p < 0.0001), whereas there was no difference in SMRP and pOPN mean values between healthy subjects and BRD patients. The performance in MPM diagnosis resulted improved by the combination of the two markers. The results of our study should be confirmed by a larger scale and, possibly, a multicenter study, which could better take into consideration the influence of some possible confounding factors such as glomerular filtration rate and other blood parameters. We combined SMRP and pOPN dosages to increase diagnostic accuracy. This study showed for the first time that combined SMRP and pOPN measurements can increase both sensitivity and specificity in terms of combined risk index.

The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma

Malignant pleural mesothelioma (MPM) remains a cancer of poor prognosis. It is hoped that implementation of effective screening biomarkers will lead to earlier diagnoses and improved outcomes. Serum-measured soluble mesothelin-related peptide (SMRP) has been demonstrated to have excellent specificity for MPM, but poor sensitivity precludes its use as a screening biomarker. Using a case series of MPM patients from the International Mesothelioma Program at the Brigham and Women's hospital, we sought to determine whether epigenetic change at the MSLN gene in patient tumors is responsible for the poor sensitivity of SMRP. We identified three potential target regions for CpG methylation silencing in the MSLN promoter, one of which was amenable to bisulfite pyrosequencing and located 214 bp upstream of the transcription start site. MSLN promoter methylation was significantly higher in normal pleura than tumor tissue (P < 6.0x10-9). Next, we compared cases according to serum SMRP status and observed that MSLN methylation was significantly higher among tumors from patients testing negative for SMRP (<1.5nM) versus those that were SMRP positive (P < 0.03). These results demonstrate that MSLN is normally methylated in the pleura, and that methylation is lost in most tumors. However, in a subset of tumors methylation is retained, and this mechanism explains the poor sensitivity of the SMRP assay. These results may lead to additional biomarker targets that will resolve the poor sensitivity of the SMRP assay and allow implementation of screening among exposed populations.

Biomarkers in Malignant Mesothelioma: Diagnostic and Prognostic Role of Soluble Mesothelin-Related Peptide

Soluble mesothelin-related peptide (SMRP) is a biomarker that has been proposed for differential diagnosis from pleural metastatic cancer, as well as prognosis and treatment monitoring of malignant pleural mesothelioma (MM). The aim of this study was to evaluate the role of SMRP in clinic management of MM. We assayed the SMRP concentrations in 354 subjects: 109 healthy volunteers with no history of exposure to asbestos, 26 patients with previous occupational asbestos exposure but who were free from pleural or parenchymal disease, 48 patients with asbestosis, 110 patients with pleural plaques, 25 patients with lung cancer, and 36 patients with MM. We also tested SMRP titers in 2 patients with MM at 5 different times of the disease, to evaluate the trend of the biomarker in the course of therapy. Our data confirm previous experiences with the use of SMRP as a diagnostic marker of MM. Low SMRP levels at diagnosis seem to have a positive prognostic significance.