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BackgroundThere is a medical need for diagnostic biomarkers in lung cancer. We evaluated the diagnostic performance of complement activation fragments.MethodsWe assessed complement activation in four bronchial epithelial and seven lung cancer cell lines. C4d, a degradation product of complement activation, was determined in 90 primary lung tumors; bronchoalveolar lavage supernatants from patients with lung cancer (n = 50) and nonmalignant respiratory diseases (n = 22); and plasma samples from advanced (n = 50) and early lung cancer patients (n = 84) subjects with inflammatory lung diseases (n = 133), and asymptomatic individuals enrolled in a lung cancer computed tomography screening program (n = 190). Two-sided P values were calculated by Mann-Whitney U test.ResultsLung cancer cells activated the classical complement pathway mediated by C1q binding that was inhibited by phosphomonoesters. Survival was decreased in patients with high C4d deposition in tumors (hazard ratio [HR] = 3.06; 95% confidence interval [CI] = 1.18 to 7.91). C4d levels were increased in bronchoalveolar lavage fluid from lung cancer patients compared with patients with nonmalignant respiratory diseases (0.61 ± 0.87 vs 0.16 ± 0.11 µg/mL; P < .001). C4d levels in plasma samples from lung cancer patients at both advanced and early stages were also increased compared with control subjects (4.13 ± 2.02 vs 1.86 ± 0.95 µg/mL, P < 0.001; 3.18 ± 3.20 vs 1.13 ± 0.69 µg/mL, P < .001, respectively). C4d plasma levels were associated with shorter survival in patients at advanced (HR = 1.59; 95% CI = 0.97 to 2.60) and early stages (HR = 5.57; 95% CI = 1.60 to 19.39). Plasma C4d levels were reduced after surgical removal of lung tumors (P < .001) and were associated with increased lung cancer risk in asymptomatic individuals with (n = 32) or without lung cancer (n = 158) (odds ratio = 4.38; 95% CI = 1.61 to 11.93).ConclusionsComplement fragment C4d may serve as a biomarker for early diagnosis and prognosis of lung cancer.

Original publication




Journal article


Journal of the National Cancer Institute

Publication Date





1385 - 1393


Affiliations of authors: Division of Oncology, Center for Applied Medical Research, Pamplona, Spain (DA, MJP, LC, JA, LMM, RP); Department of Histology and Pathology (MJP, JA, LMM) and Department of Biochemistry and Genetics (RP) School of Medicine, University of Navarra, Pamplona, Spain; Department of Oncology (JLP), Department of Pathology (MDL), Department of Thoracic Surgery (WT), Department of Pulmonary Medicine (JPdT, JJZ) Clínica Universidad de Navarra, Pamplona, Spain; Thoracic Program, Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN (PPM); Department of Medicine, University of Valencia, Valencia, Spain (CC); Department of Medical Oncology, Hospital General Universitario de Valencia, Valencia, Spain (CC); Molecular Oncology Laboratory, Fundación para la Investigación del Hospital General Universitario de Valencia, Valencia, Spain (EJL).


Bronchoalveolar Lavage Fluid, Humans, Lung Neoplasms, Peptide Fragments, Neoplasm Staging, Prognosis, Predictive Value of Tests, Complement Activation, Complement Pathway, Classical, Adult, Aged, Middle Aged, Female, Male, Complement C4b, Early Detection of Cancer, Biomarkers, Tumor