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Published on: September 25, 2018
Investigation of complement activation product c4d as a diagnostic and prognostic biomarker for lung cancer
Daniel Ajona1, María J Pajares, Leticia Corrales
1Affiliations 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).
Background:
There is a medical need for diagnostic biomarkers in lung cancer. We evaluated the diagnostic performance of complement activation fragments.
Methods:
We 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.
Results:
Lung 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).
Conclusions:
Complement fragment C4d may serve as a biomarker for early diagnosis and prognosis of lung cancer.
