Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma

Lory Santarelli, Sara Staffolani, Elisabetta Strafella, Linda Nocchi, Nicola Manzella, Paola Grossi, Massimo Bracci, Elettra Pignotti, Renata Alleva, Battista Borghi, Cecilia Pompili, Armando Sabbatini, Corrado Rubini, Lina Zuccatosta, Elisabetta Bichisecchi, Matteo Valentino, Keith Horwood, Manola Comar, Massimo Bovenzi, Lan Feng DongJiri Neuzil, Monica Amati, Marco Tomasetti

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Objectives: 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. Materials and 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. Results and conclusion: 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.

Original languageEnglish
Pages (from-to)457-464
Number of pages8
JournalLung Cancer
Volume90
Issue number3
DOIs
Publication statusPublished - Dec 1 2015

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Epigenomics
Biomarkers
Proteins
Asbestos
Healthy Volunteers
Serum
Malignant Mesothelioma
mesothelin
Thrombomodulin
MicroRNAs
ROC Curve
Lung Neoplasms
Neoplasms
Logistic Models
Regression Analysis
Population

Keywords

  • Early diagnosis
  • Epigenetic biomarkers
  • Lung cancer
  • Mesothelin
  • Mesothelioma
  • Methylated gene thrombomodulin
  • miR-126

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

Santarelli, L., Staffolani, S., Strafella, E., Nocchi, L., Manzella, N., Grossi, P., ... Tomasetti, M. (2015). Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma. Lung Cancer, 90(3), 457-464. https://doi.org/10.1016/j.lungcan.2015.09.021

Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma. / Santarelli, Lory; Staffolani, Sara; Strafella, Elisabetta; Nocchi, Linda; Manzella, Nicola; Grossi, Paola; Bracci, Massimo; Pignotti, Elettra; Alleva, Renata; Borghi, Battista; Pompili, Cecilia; Sabbatini, Armando; Rubini, Corrado; Zuccatosta, Lina; Bichisecchi, Elisabetta; Valentino, Matteo; Horwood, Keith; Comar, Manola; Bovenzi, Massimo; Dong, Lan Feng; Neuzil, Jiri; Amati, Monica; Tomasetti, Marco.

In: Lung Cancer, Vol. 90, No. 3, 01.12.2015, p. 457-464.

Research output: Contribution to journalArticle

Santarelli, L, Staffolani, S, Strafella, E, Nocchi, L, Manzella, N, Grossi, P, Bracci, M, Pignotti, E, Alleva, R, Borghi, B, Pompili, C, Sabbatini, A, Rubini, C, Zuccatosta, L, Bichisecchi, E, Valentino, M, Horwood, K, Comar, M, Bovenzi, M, Dong, LF, Neuzil, J, Amati, M & Tomasetti, M 2015, 'Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma', Lung Cancer, vol. 90, no. 3, pp. 457-464. https://doi.org/10.1016/j.lungcan.2015.09.021
Santarelli, Lory ; Staffolani, Sara ; Strafella, Elisabetta ; Nocchi, Linda ; Manzella, Nicola ; Grossi, Paola ; Bracci, Massimo ; Pignotti, Elettra ; Alleva, Renata ; Borghi, Battista ; Pompili, Cecilia ; Sabbatini, Armando ; Rubini, Corrado ; Zuccatosta, Lina ; Bichisecchi, Elisabetta ; Valentino, Matteo ; Horwood, Keith ; Comar, Manola ; Bovenzi, Massimo ; Dong, Lan Feng ; Neuzil, Jiri ; Amati, Monica ; Tomasetti, Marco. / Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma. In: Lung Cancer. 2015 ; Vol. 90, No. 3. pp. 457-464.
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AU - Santarelli, Lory

AU - Staffolani, Sara

AU - Strafella, Elisabetta

AU - Nocchi, Linda

AU - Manzella, Nicola

AU - Grossi, Paola

AU - Bracci, Massimo

AU - Pignotti, Elettra

AU - Alleva, Renata

AU - Borghi, Battista

AU - Pompili, Cecilia

AU - Sabbatini, Armando

AU - Rubini, Corrado

AU - Zuccatosta, Lina

AU - Bichisecchi, Elisabetta

AU - Valentino, Matteo

AU - Horwood, Keith

AU - Comar, Manola

AU - Bovenzi, Massimo

AU - Dong, Lan Feng

AU - Neuzil, Jiri

AU - Amati, Monica

AU - Tomasetti, Marco

PY - 2015/12/1

Y1 - 2015/12/1

N2 - Objectives: 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. Materials and 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. Results and conclusion: 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.

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KW - Epigenetic biomarkers

KW - Lung cancer

KW - Mesothelin

KW - Mesothelioma

KW - Methylated gene thrombomodulin

KW - miR-126

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