Investigation of complement activation product c4d as a diagnostic and prognostic biomarker for lung cancer.
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.
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).
Daniel
D
Ajona
María J
MJ
Pajares
Leticia
L
Corrales
Jose L
JL
Perez-Gracia
Jackeline
J
Agorreta
Maria D
MD
Lozano
Wenceslao
W
Torre
Pierre P
PP
Massion
Juan P
JP
de-Torres
Eloisa
E
Jantus-Lewintre
Carlos
C
Camps
Javier J
JJ
Zulueta
Luis M
LM
Montuenga
Ruben
R
Pio
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000097:blood; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry*; D003167:Complement Activation; D015935:Complement C4b / Q000032:analysis*; D003171:Complement Pathway, Classical; D055088:Early Detection of Cancer; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000737:chemistry / Q000175:diagnosis* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010446:Peptide Fragments / Q000032:analysis* / Q000097:blood; D011237:Predictive Value of Tests; D011379:Prognosis
D014408:Biomarkers, Tumor; D010446:Peptide Fragments; D015935:Complement C4b; C032261:complement C4d