Value Of Serum Dickkopf-1 In Early Diagnosis And Relation With Bone Metastasis In Non-small Cell Lung Cancer

Part I Early diagnostic value of serum Dickkopf-1 in non-small cell lung cancer and its correlation with clinicopathological featuresObjective: By detecting the expression of serum Dickkopf-1(DKK-1)in patients with stage I-IIIa non-small cell carcinoma(NSCLC)and pulmonary benign nodules,we analyzed the relationship between serum DKK-1 levels and clinicopathological features of NSCLC,and explored its value in early diagnosis of NSCLC.Methods: Serum samples were collected from 418 patients with primary NSCLC,including 252 patients with stage I,77 patients with stage II,89 patients with stage IIIa.39 patients were with benign pulmonary nodules.Enzyme-Linked Immunosorbent Assay(ELISA)was used to detect serum DKK-1 levels and to compare the difference of serum DKK-1 levels between patients with stage I NSCLC and patients with benign pulmonary nodules.In addition,the relationship between the serum DKK-1 levels and the clinicopathological features of NSCLC patients was analyzed.Results:(1)There was no significant difference in age,sex and tumor size between patients with stage I NSCLC and those with benign pulmonary nodules(P > 0.05).The mean serum DKK-1 levels in patients with stage I NSCLC were 231.7pg/ml,and that of the benign pulmonary nodules group was 268.6 pg/ml.There was no significant difference between the two groups(P = 0.116).(2)According to the sex,age,pathological type,lymphovascular invasion,visceral pleura invasion,tumor size and N stage,patients with stage I-IIIa were divided into different groups.The results showed that serum DKK-1 levels were correlated with pathological type(P = 0.037),tumor size(P = 0.001)and N stage(P = 0.002).Conclusion:(1)Serum DKK-l levels in patients with stage I NSCLC were not significantly different from that in patients with benign pulmonary nodules,and could not be used as a clinical marker for early diagnosis of NSCLC.(2)Serum DKK-l in NSCLC patients was related to the tumor size and clinical stage,which may play an important role in the growth and metastasis of lung cancer.Part II Diagnostic significance and prognostic value of serum Dickkopf-1 in non-small cell lung cancer patients with bone metastasesObjectives: The study was designed to evaluate the association between serum Dickkopf-1(DKK-1)and non-small cell lung cancer(NSCLC)bone metastases.Materials and Methods: Serum DKK-1 levels were quantified in 318 NSCLC patients,140 with osseous metastases,178 with extraosseous metastases.The Receiver Operating Characteristic(ROC)curve enabled us to identify a threshold value to distinguish patients with bone metastases.Results:(1)The mean level of serum DKK-1 was 371.44 pg/ml in patients with osseous metastases and 260.71 pg/ml in patients with extraosseous metastases.Serum DKK-1 increased significantly with the presence of bone metastases(P < 0.001).Serum DKK-1 did not correlate with N stage(P = 0.455),T stage(P = 0.761),pleura metastases(P = 0.472),lung metastases(P = 0.928),brain metastases(P = 0.186),liver metastases(P = 0.800)or adrenal gland metastases(P = 0.838).ROC curves showed that the optimum cutoff was 311.8 pg/ml,area under curve was 0.791,95%confidence interval(CI)was 0.739-0.843,with sensitivity 77.1% and specificity71.4%.(2)In the osseous metastases group,45 patients had a solitary bone metastasis and 95 had multiple bone metastases;49 patients had isolated bone metastases and 91 had bone and visceral or cerebral metastases.Serum DKK-1 levels were classified as high or low in relation to the cutoff value,which was based on the results of ROC analysis.Patients with osseous metastases(n = 140)were divided into groups based on serum DKK-1 levels,the high level group(DKK-1 > 311.8 pg/ml,n = 108)and the low level group(DKK-1 ? 311.8 pg/ml,n = 32).The relationship between serum DKK-1 levels and clinicopathological characteristics of these patients were then analyzed,and results showed high serum DKK-1 levels were significantly correlated with the number of bone metastases(P = 0.042).There was no association with metastatic pattern and the distribution of bone metastases.(3)The median survival time of patents with bone metastases was 15.2 months.Kaplan–Meier analysis indicated that high DKK-1 levels were correlated with poor overall survival(P =0.025).Multivariate Cox regression analysis indicated that ECOG PS(HR = 3.689;P= 0.001),serum DKK-1 level(HR = 1.665;P = 0.027),number of bone metastases(HR = 1.895;P = 0.004)and metastatic pattern(HR = 1.238;P = 0.046)were independent prognostic factors for overall survival in NSCLC patients with bone metastases.Conclusions:(1)Serum DKK-1 was a potential serum biomarker to detect NSCLC bone metastases,and measuring both serum DKK-1 and CEA could improve the overall sensitivity for detecting bone metastases.(2)Serum DKK-1 was a good predictor of poor prognosis in NSCLC patients with bone metastases.