title: Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma.
abstract: OBJECTIVE
  Malignant mesothelioma (MM) is a highly aggressive tumor with poor prognosis. A major challenge is the development and application of early and highly reliable diagnostic marker(s). Serum biomarkers, such as 'soluble mesothelin-related proteins' (SMRPs), is the most studied and frequently used in MM. However, the low sensitivity of SMRPs for early MM limits its value; therefore, additional biomarkers are required. In this study, two epigenetically regulated markers in MM (microRNA-126, miR-126, and methylated thrombomodulin promoter, Met-TM) were combined with SMRPs and evaluated as a potential strategy to detect MM at an early stage.
  
  
  METHODS
  A total of 188 subjects, including 45 MM patients, 99 asbestos-exposed subjects, and 44 healthy controls were prospectively enrolled, serum samples collected, and serum levels of SMRPs, miR-126 and Met-TM evaluated. Logistic regression analysis was performed to evaluate the diagnostic value of the three biomarkers. Using this approach, the performance of the '3-biomarker classifier' was tested by calculating the overall probability score of the MM and control samples, respectively, and the ROC curve was generated.
  
  
  CONCLUSIONS
  The combination of the three biomarkers was the best predictor to differentiate MM patients from asbestos-exposed subjects and healthy controls. The accuracy and cancer specificity was confirmed in a second validation cohort and lung cancer population. We propose that the combination of the two epigenetic biomarkers with SMRPs as a diagnosis for early MM overcomes the limitations of using SMRPs alone.
authors.affiliation: Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Lory
authors.initials: L
authors.lastname: Santarelli
authors.affiliation: Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Staffolani
authors.affiliation: Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Strafella
authors.affiliation: Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Linda
authors.initials: L
authors.lastname: Nocchi
authors.affiliation: Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Manzella
authors.affiliation: Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Grossi
authors.affiliation: Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bracci
authors.affiliation: Department of Anesthesiology Research Unit, IRCCS Orthopaedic Institute Rizzoli, Bologna, Italy.
authors.forename: Elettra
authors.initials: E
authors.lastname: Pignotti
authors.affiliation: Department of Anesthesiology Research Unit, IRCCS Orthopaedic Institute Rizzoli, Bologna, Italy.
authors.forename: Renata
authors.initials: R
authors.lastname: Alleva
authors.affiliation: Department of Anesthesiology Research Unit, IRCCS Orthopaedic Institute Rizzoli, Bologna, Italy.
authors.forename: Battista
authors.initials: B
authors.lastname: Borghi
authors.affiliation: Division of Thoracic Surgery, United Hospitals, Ancona 60126, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Pompili
authors.affiliation: Division of Thoracic Surgery, United Hospitals, Ancona 60126, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Sabbatini
authors.affiliation: Department of Biomedical Sciences and Public Health, Section of Anatomical Pathology, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Corrado
authors.initials: C
authors.lastname: Rubini
authors.affiliation: Pulmonary Diseases Unit, Department of Immunoallergic and Respiratory Diseases, United Hospitals, Ancona, Italy.
authors.forename: Lina
authors.initials: L
authors.lastname: Zuccatosta
authors.affiliation: Division of Radiology, United Hospitals, Ancona, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Bichisecchi
authors.affiliation: Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Valentino
authors.affiliation: Greenslopes Private Hospital, Qld, Australia.
authors.forename: Keith
authors.initials: K
authors.lastname: Horwood
authors.affiliation: Department of Medical Sciences, University of Trieste, Trieste, Italy.
authors.forename: Manola
authors.initials: M
authors.lastname: Comar
authors.affiliation: Department of Medical Sciences, University of Trieste, Trieste, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bovenzi
authors.affiliation: Mitochondria, Apoptosis and Cancer Research Group, School of Medical Science and Griffith Health Institute, Griffith University, Southport, Qld, Australia.
authors.forename: Lan-Feng
authors.initials: LF
authors.lastname: Dong
authors.affiliation: Mitochondria, Apoptosis and Cancer Research Group, School of Medical Science and Griffith Health Institute, Griffith University, Southport, Qld, Australia; Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague 4, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Neuzil
authors.affiliation: Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Amati
authors.affiliation: Department of Clinical and Molecular Sciences, Polytechnic University of Marche, Ancona, Italy. Electronic address: m.tomasetti@univpm.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Tomasetti
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D058851:GPI-Linked Proteins / Q000097:blood / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics* / Q000628:therapy; D008297:Male; D000090204:Mesothelin; D008654:Mesothelioma / Q000097:blood / Q000175:diagnosis* / Q000209:etiology / Q000235:genetics* / Q000628:therapy; D000086002:Mesothelioma, Malignant; D035683:MicroRNAs / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000097:blood; D011379:Prognosis; D015203:Reproducibility of Results
chemical_list: D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; D000090204:Mesothelin; D035683:MicroRNAs; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C120809:ABCC5 protein, human; C527111:MIRN126 microRNA, human
keywords: Early diagnosis; Epigenetic biomarkers; Lung cancer; Mesothelin; Mesothelioma; Methylated gene thrombomodulin; miR-126