Yu-Hui Peng

Autoantibodies as Potential Biomarkers for the Early Detection of Esophageal Squamous Cell Carcinoma

OBJECTIVES:Esophageal squamous cell carcinoma (ESCC) is one of the most frequent causes of cancer death worldwide and effective diagnosis is needed. We assessed the diagnostic potential of an autoantibody panel that may benefit early diagnosis.METHODS:We analyzed data for patients with ESCC and normal controls in a test cohort and a validation cohort. Autoantibody levels were measured against a panel of six tumor-associated antigens (p53, NY-ESO-1, matrix metalloproteinase-7 (MMP-7), heat shock protein 70 (Hsp70), peroxiredoxin VI (Prx VI), and BMI1 polycomb ring finger oncogene (Bmi-1)) by enzyme-linked immunosorbent assay.RESULTS:We assessed serum autoantibodies in 513 participants: 388 with ESCC and 125 normal controls. The validation cohort comprised 371 participants: 237 with ESCC, and 134 normal controls. Autoantibodies to at least 1 of 6 antigens demonstrated a sensitivity/specificity of 57% (95% confidence interval (CI): 52–62%)/95% (95% CI: 89–98%) and 51% (95% CI: 45–57%)/96% (95% CI: 91–99%) in the test and validation cohorts, respectively. Measurement of the autoantibody panel could differentiate early-stage ESCC patients from normal controls (sensitivity 45% (95% CI: 32–59%) and specificity 95% (95% CI: 89–98%) in the test cohort; 46% (95% CI: 35–58%) and 96% (95% CI: 91–99%) in the validation cohort). In either cohort, no significant differences were seen when patients were subdivided by age, gender, smoking status, size of tumor, site of tumor, depth of tumor invasion, histological grade, lymph node status, TNM stage, or early-stage and late-stage groups.CONCLUSIONS:Measurement of an autoantibody response to multiple tumor-associated antigens in an optimized panel assay, to help discriminate early-stage ESCC patients from normal controls, may aid in early detection of ESCC.

Autoantibody Signatures Combined with Epstein–Barr Virus Capsid Antigen-IgA as a Biomarker Panel for the Detection of Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is prevalent in Southern China and Southeast Asia, and autoantibody signatures may improve early detection of NPC. In this study, serum levels of autoantibodies against a panel of six tumor-associated antigens (p53, NY-ESO-1, MMP-7, Hsp70, Prx VI, and Bmi-1) and Epstein–Barr virus capsid antigen-IgA (VCA-IgA) were tested by enzyme-linked immunosorbent assay in a training set (220 NPC patients and 150 controls) and validated in a validation set (90 NPC patients and 68 controls). We used receiver-operating characteristics (ROC) to calculate diagnostic accuracy. ROC curves showed that use of these 6 autoantibody assays provided an area under curve (AUC) of 0.855 [95% confidence interval (CI), 0.818–0.892], 68.2% sensitivity, and 90.0% specificity in the training set and an AUC of 0.873 (95% CI, 0.821–0.925), 62.2% sensitivity, and 91.2% specificity in the validation set. Moreover, the autoantibody panel maintained diagnostic accuracy for VCA-IgA–negative NPC patients [0.854 (0.809–0.899), 67.8%, and 90.0% in the training set; 0.879 (0.815–0.942), 67.4%, and 91.2% in the validation set]. Importantly, combination of the autoantibody panel and VCA-IgA improved diagnostic accuracy for NPC versus controls compared with the autoantibody panel alone [0.911 (0.881–0.940), 81.4%, and 90.0% in the training set; 0.919 (0.878–0.959), 78.9%, and 91.2% in the validation set), as well as for early-stage NPC (0.944 (0.894–0.994), 87.9%, and 94.0% in the training set; 0.922 (0.808–1.000), 80.0%, and 92.6% in the validation set]. These results reveal autoantibody signatures in an optimized panel that could improve the identification of VCA-IgA–negative NPC patients, may aid screening and diagnosis of NPC, especially when combined with VCA-IgA. Cancer Prev Res; 8(8); 729–36. ©2015 AACR.

Combined detection of serum Dickkopf-1 and its autoantibodies to diagnose esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) can be treated effectively if diagnosed at an early stage. We evaluated whether measurement of Dickkopf‐1 (DKK‐1) in combination of DKK‐1 autoantibodies in serum may benefit early diagnosis of ESCC. Serum DKK‐1 and DKK‐1 autoantibodies were measured by enzyme‐linked immunosorbent assay in a training cohort (185 ESCC samples vs. 97 normal controls) and validated in a validation cohort (104 ESCC samples vs. 53 normal controls). Receiver operating characteristic (ROC) was applied to calculate diagnostic accuracy. Testing of DKK‐1 and DKK‐1 autoantibodies together could differentiate ESCC from normal controls (area under the ROC curve [AUC] 0.769, 95% confidence interval (CI), 0.715–0.823, 50.3% sensitivity, and 90.7% specificity in the training cohort; AUC 0.752, 95% CI, 0.675–0.829, 50.0% sensitivity, and 84.9% specificity in the validation cohort). Importantly, the diagnostic performance of the combination of DKK‐1 and DKK‐1 autoantibodies persisted in early ESCC patients (AUC 0.780, 95% CI, 0.699–0.862, 50.0% sensitivity, and 90.7% specificity in the training cohort; AUC 0.745, 95% CI, 0.626–0.865, 53.8% sensitivity, and 84.9% specificity in the validation cohort). Furthermore, the levels of serum DKK‐1 or DKK‐1 autoantibody after surgical resection were lower, respectively, compared with the corresponding preoperative samples (P < 0.05). Our results suggest that measurement of DKK‐1 combined with DKK‐1 autoantibodies is a potentially valuable tool for the early detection of ESCC.

Tumor-associated autoantibodies against Fascin as a novel diagnostic biomarker for esophageal squamous cell carcinoma

BACKGROUND AND OBJECTIVE Autoantibodies against tumor-associated antigens (TAAs) have been found in many kinds of cancers, and might serve as biomarkers for early cancer diagnosis. The present study was carried out to test if there is any relation between autoantibodies against Fascin and esophageal squamous cell carcinoma (ESCC). METHODS One hundred and forty-nine patients with ESCC and 98 control subjects were recruited in the study. The levels of circulating autoantibodies against Fascin were measured by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic (ROC) was used to calculate diagnostic accuracy. RESULT The levels of autoantibodies against Fascin in patients with ESCC were significantly higher than in control subjects (P<0.001). Measurement of autoantibodies against Fascin provided an area under the curve (AUC) of 0.636, [95% confidence interval (CI): 0.568-0.704] 24.8% sensitivity (95% CI: 18.3%-37.2%) and 99.0% specificity (95% CI: 93.6%-99.9%). Moreover, serum level of autoantibodies against Fascin in early-stage ESCC was significantly higher than that of normal controls (P<0.05). The positive rates of autoantibodies against Fascin were correlated with age (P<0.05), but not with gender, tumor size, tumor site, histological grade, T stage, N stage or TNM stage (P>0.05). CONCLUSIONS Our results suggest that Fascin autoantibody may be a potential biomarker for the early detection of ESCC.

Diagnostic Value of Autoantibodies against Ezrin in Esophageal Squamous Cell Carcinoma

Esophageal squamous cell carcinoma (ESCC), one of the most common malignancies worldwide, is a highly aggressive and homogeneous entity occurring in esophageal squamous epithelium, and a reliable noninvasive test for early detection is needed. A recent study showed that serum autoantibodies against Ezrin could be detected in patients with pancreatic cancer. Here, we assessed whether autoantibodies against Ezrin could have diagnostic relevance for early ESCC. We analyzed autoantibodies against Ezrin in sera of 98 normal controls and 149 patients with ESCC. Ezrin autoantibodies levels were evaluated by enzyme-linked immunosorbent assay (ELISA). Results showed that higher levels of autoantibodies against Ezrin were observed in serum samples from patients with ESCC than in serum from normal controls (P < 0.0001). Based on a cutoff value of 0.319, the sensitivity and specificity of autoantibodies against Ezrin for diagnosis of ESCC were 27.5% and 95.9%, respectively. Compared with normal controls, the positive rate of autoantibodies against Ezrin was significantly elevated in patients with early-stage ESCC (P < 0.0001). Moreover, there was no significant difference of positivity of autoantibodies against Ezrin in ESCC patients categorized according to age, gender, tumor size, tumor invasion depth, tumor site, histological grade, lymph node status, or tumor stage. Our study indicates that the presence of autoantibodies against Ezrin is significantly associated with ESCC.

Diagnostic and prognostic value of serum L1-cell adhesion molecule in esophageal squamous cell carcinoma

OBJECTIVE L1 cell adhesion molecule (L1CAM) has been found to be dysregulated in several types of human cancers. Here, we aimed to determine the level of soluble L1CAM in serum of patients with esophageal squamous cell carcinoma (ESCC). METHODS Serum levels of L1CAM were determined by an enzyme-linked immunosorbent assay (ELISA) in 191 patients with ESCC and 94 normal controls. Receiver operating characteristics (ROC) was employed to calculate diagnostic accuracy. Cumulative survival time was calculated by the Kaplan-Meier method and analyzed by the logrank test. RESULTS Levels of L1CAM were significantly lower in all ESCC patients than in normal controls (P < 0.001). Detection of serum L1CAM provided a sensitivity of 28.3%, a specificity of 90.4% and an area under the curve (AUC) of 0.644 (95% CI: 0.579-0.710) in diagnosing ESCC. Similar results were observed in the diagnosis of early-stage ESCC (26.2% sensitivity, 90.4% specificity, and an AUC of 0.629). Moreover, decreased level of L1CAM was correlated with depth of tumor invasion (P < 0.05). Kaplan-Meier analysis showed that lower serum L1CAM level was significantly related to shorter overall survival time (P = 0.036) and disease-free survival time (P = 0.021) of ESCC patients. CONCLUSIONS Our study demonstrated that serum L1CAM might serve as a potential biomarker for the diagnosis and prognosis of ESCC.

Fascin and esophageal squamous cell carcinoma: Cheng et al.

In a cancer prevalence survey, China was recognized to have a high incidence of esophageal cancer. Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer and accounts for the vast majority of cases every year. ESCC cases in China contribute toward nearly half of all new global cases each year. As one of the higher ESCC prevalence regions in China, the Chaoshan District of Guangdong Province is the only area on the Chinese coastline with such a distinguished profile. Our laboratory, which is located in the Chaoshan District, studies the biological function, molecular basis, regulation mechanisms, and clinical significance of abnormally expressed cellular cytoskeleton binding proteins in ESCC, such as ezrin, fascin, LCN2, LOXL2, and DSC2. In the present review, we summarized studies on fascin in ESCC reported by our laboratory and other laboratories around the world. In ESCC, fascin expression is highly upregulated at the mRNA and protein levels, and can serve as an early biomarker for tumor invasion and metastasis. Furthermore, fascin transcription is directly activated through Sp1 binding to its promoter; this process is enhanced through the phosphorylation of Sp1 by the epidermal grown factor‐activated Mitogen‐activated protein kinase (MAPK)/Extracellular signal‐regulated kinase (ERK) (MEK)‐ERK1/2 signaling pathway. Furthermore, the function of fascin is also regulated by post‐translational modifications. For instance, the phosphorylation of several amino acid residues of fascin inhibits ESCC cell behavior and filopodia formation. However, whether other types of fascin modifications exist remains unknown and requires further study.