Elevated levels of the complement activation product C4d in bronchial fluids for the diagnosis of lung cancer
Ajona D(1), Razquin C(1), Pastor MD(2), Pajares MJ(3), Garcia J(4), Cardenal F(5), Fleischhacker M(6), Lozano MD(7), Zulueta JJ(4), Schmidt B(6), Nadal E(5), Paz-Ares L(2), Montuenga LM(3), Pio R(8).
(1) Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), Pamplona, Spain.
(2) Laboratorio de Oncologia Molecular y Nuevas Terapias, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Sevilla, Spain.
(3) Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), Pamplona, Spain; Department of Histology and Pathology, School of Medicine, University of Navarra, Pamplona, Spain.
(4) Department of Pulmonary Medicine, Clinica Universidad de Navarra, Pamplona, Spain.
(5) Medical Oncology Department, Catalan Institute of Oncology-IDIBELL, Barcelona, Spain.
(6) Molecular Biology Laboratory, Universitätsklinikum Halle, Saale, Germany.
(7) Department of Pathology, Clinica Universidad de Navarra, Pamplona, Spain.
(8) Program in Solid Tumors and Biomarkers, Center for Applied Medical Research (CIMA), Pamplona, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
Molecular markers in bronchial fluids may contribute to the diagnosis of lung cancer. We previously observed a significant increase of C4d-containing complement degradation fragments in bronchoalveolar lavage (BAL) supernatants from lung cancer patients in a cohort of 50 cases and 22 controls (CUN cohort).
The present study was designed to determine the diagnostic performance of these complement fragments (hereinafter jointly referred as C4d) in bronchial fluids. C4d levels were determined in BAL supernatants from two independent cohorts: the CU cohort (25 cases and 26 controls) and the HUVR cohort (60 cases and 98 controls). A series of spontaneous sputum samples from 68 patients with lung cancer and 10 controls was also used (LCCCIO cohort). Total protein content, complement C4, complement C5a, and CYFRA 21-1 were also measured in all cohorts.
C4d levels were significantly increased in BAL samples from lung cancer patients. The area under the ROC curve was 0.82 (95%CI = 0.71-0.94) and 0.67 (95%CI = 0.58-0.76) for the CU and HUVR cohorts, respectively. In addition, unlike the other markers, C4d levels in BAL samples were highly consistent across the CUN, CU and HUVR cohorts. Interestingly, C4d test markedly increased the sensitivity of bronchoscopy in the two cohorts in which cytological data were available (CUN and HUVR cohorts).
Finally, in the LCCCIO cohort, C4d levels were higher in sputum supernatants from patients with lung cancer (area under the ROC curve: 0.7; 95%CI = 0.56-0.83). In conclusion, C4d is consistently elevated in bronchial fluids from lung cancer patients and may be used to improve the diagnosis of the disease.
CITATION PLoS One. 2015 Mar 23;10(3):e0119878. doi: 10.1371/journal.pone.0119878.