Research Papers:

Complement C4d-specific antibodies for the diagnosis of lung cancer

Daniel Ajona _, Marcin Okrój, María J. Pajares, Jackeline Agorreta, María D. Lozano, Javier J. Zulueta, Carla Verri, Luca Roz, Gabriella Sozzi, Ugo Pastorino, Pierre P. Massion, Luis M. Montuenga, Anna M. Blom and Ruben Pio

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Oncotarget. 2018; 9:6346-6355. https://doi.org/10.18632/oncotarget.23690

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Daniel Ajona1,2,*, Marcin Okrój3,4,*, María J. Pajares1,5, Jackeline Agorreta1,5, María D. Lozano6, Javier J. Zulueta7, Carla Verri8, Luca Roz8, Gabriella Sozzi8, Ugo Pastorino9, Pierre P. Massion10, Luis M. Montuenga1,5, Anna M. Blom3,# and Ruben Pio1,2,#

1Program in Solid Tumors, Center for Applied Medical Research (CIMA), CIBERONC, and Navarra’s Health Research Institute (IDISNA), Pamplona, Spain

2Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain

3Lund University, Department of Translational Medicine, Section of Medical Protein Chemistry, Malmö, Sweden

4Department of Medical Biotechnology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Poland

5Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain

6Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain

7Department of Pulmonary Medicine, Clínica Universidad de Navarra, Pamplona, Spain

8Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

9Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

10Thoracic Program, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, USA

*These authors contributed equally to this work

#These authors share senior authorship

Correspondence to:

Daniel Ajona, email: [email protected]

Anna M. Blom, email: [email protected]

Keywords: lung cancer; diagnosis; biomarker; complement C4d; indeterminate pulmonary nodules

Abbreviations: AU: Arbitrary units; CI: confidence interval; CT: computed tomography; MILD: Multicenter Italian Lung Detection; VMUC: Vanderbilt University Medical Center

Received: November 10, 2017     Accepted: December 22, 2017     Published: December 26, 2017


Development of molecular markers that help to identify high-risk individuals or diagnose indeterminate pulmonary nodules could have a major impact on lung cancer clinical management. In this study, we evaluated the diagnostic potential of a newly-developed ELISA that specifically detects complement C4d. We measured this marker in five independent cohorts of plasma and bronchoalveolar lavage samples from lung cancer patients and controls. In case-control studies, the area under the ROC curve for the diagnosis of lung cancer was 0.82 (95%CI = 0.72–0.92) in plasma samples, and 0.80 (95%CI = 0.69 to 0.90) in bronchoalveolar lavage fluids. In a set of plasma samples from the MILD CT-screening trial, the assay was unable to discriminate between asymptomatic high-risk individuals with or without early stage lung cancer. On the contrary, in two independent cohorts of individuals with indeterminate pulmonary nodules, plasma samples from patients with lung cancer nodules presented higher levels of C4d than those from patients with benign nodules. Using a target population of patients with 8 to 30 mm nodules, the test identified likely benign lung nodules with 84% negative predictive value and 54% positive predictive value, at 89% specificity and 44% sensitivity. In conclusion, the specific determination of C4d may serve as an adjunct to current clinical practice in the diagnosis of indeterminate pulmonary nodules.

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