title: Serum ENA78/CXCL5, SDF-1/CXCL12, and their combinations as potential biomarkers for prediction of the presence and distant metastasis of primary gastric cancer.
abstract: BACKGROUND
  Chemokines play important roles in cancer development and progression. Epithelial-derived neutrophil-activating peptide-78 (ENA78/CXCL5) and stromal cell-derived factor (SDF-1/CXCL12) supposedly contribute to gastric cancer (GC) development and progression. This study aims to evaluate serum levels of ENA78/CXCL5 and SDF-1/CXCL12 along the GC carcinogenesis, and analyze their clinical significance, and diagnostic potentials through human serum samples.
  
  
  METHODS
  A total of 300 subjects were enrolled in this study. Serum levels of ENA78/CXCL5 and SDF-1/CXCL12, measured by chemiluminescent immunoassay, were compared among 4 disease groups; normal, high-risk (intestinal metaplasia and adenoma), early GC (EGC), and advanced GC (AGC) groups in both training (n=25 per group) and validation dataset (n=70, 30, 50, 50, respectively) by ANOVA test (post hoc Bonferroni). Correlations between serum ENA78/CXCL5 or SDF-1/CXCL12 levels and clinicopathological parameters of GC patients were evaluated (Spearman's correlation; γs). To validate the diagnostic accuracy, receiver operating characteristic (ROC) curve and logistic regression analysis was performed.
  
  
  RESULTS
  Serum ENA78/CXCL5 and SDF-1/CXCL12 levels were significantly higher in AGC groups than EGC, high-risk and normal groups in both training and validation dataset (Bonferroni, from p<0.01 to p<0.001). Clinicopathologically, serum ENA78/CXCL5 was correlated with T-stage (γs=0.231, p=0.021) and distant metastasis (γs=0.357, p<0.001), while serum SDF-1/CXCL12 was correlated with lymph node (γs=0.220, p=0.029) and distant (γs=0.425, p<0.001) metastasis. ROC curve and logistic regression demonstrated that serum ENA78/CXCL5 and SDF-1/CXCL12 showed higher diagnostic accuracy compared with carcinoembryonic antigen (CEA) in predicting GC. Serum ENA78/CXCL5 could predict both the presence of GC and distant metastasis, while serum SDF-1/CXCL12 could mainly predict its distant metastasis. All combination of serum ENA78/CXCL5, SDF-1/CXCL12, and CEA achieved 92.8% specificity at 75.0% sensitivity to predict distant metastasis of GC.
  
  
  CONCLUSIONS
  Combinations of initial serum ENA78/CXCL5, SDF-1/CXCL12, and CEA before any treatment for GC can produce valuable serum biomarker panels to predict the presence and distant metastasis of GC.
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jong-Baeck
authors.initials: JB
authors.lastname: Lim
authors.affiliation: Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Division of Gastroenterology, International St. Mary's Hospital, Incheon Metropolitan City, Republic of Korea. Electronic address: may3md@naver.com.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Chung
mesh_terms: D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000097:blood*; D002272:Carcinoembryonic Antigen / Q000097:blood; D054377:Chemokine CXCL12 / Q000097:blood*; D054365:Chemokine CXCL5 / Q000097:blood*; D019992:Databases as Topic; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D009362:Neoplasm Metastasis; D012372:ROC Curve; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013274:Stomach Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; C515255:CXCL12 protein, human; C486263:CXCL5 protein, human; D002272:Carcinoembryonic Antigen; D054377:Chemokine CXCL12; D054365:Chemokine CXCL5
keywords: Biomarker; Distant metastasis; Epithelial-derived neutrophil-activating peptide-78; Gastric cancer; Stromal cell-derived factor