Novel circulating peptide biomarkers for esophageal squamous cell carcinoma revealed by a magnetic bead-based MALDI-TOFMS assay

Abstract

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant neoplasms worldwide. Patients are often diagnosed at advanced stages with poor prognosis due to the absence of obvious early symptoms. Here, we applied a high-throughput serum peptidome analysis to identify circulating peptide markers of ESCC. Weak cationic exchange magnetic beads coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used for two-stage proteotypic peptide profiling in complex serum samples collected from 477 cancer patients and healthy controls. We established a genetic algorithm model containing three significantly differentially expressed peptides at 1,925.5, 2,950.6 and 5,900.0 Da with a sensitivity and specificity of 97.00% and 95.92% in the training set and 97.03% and 100.00% in the validation set, respectively. The model's diagnostic capability was significantly better than SCC-Ag and Cyfra 21–1, especially for early stage ESCC, with an achieved sensitivity of 96.94%. Subsequently, these peptides were identified as fragments of AHSG, TSP1 and FGA by linear ion trap-orbitrap hybrid tandem mass spectrometry. Notably, increased tissue and serum levels of TSP1 in ESCC were verified and correlated with disease progression. In addition, tissue TSP1 was an independent poor prognostic factor in ESCC. In conclusion, the newly established circulating peptide panel and identified proteins could serve as potential biomarkers for the early detection and diagnosis of ESCC. Nevertheless, a larger cohort will be required for further unequivocal validation of their clinical application.

Autophagy modulators for the treatment of oral and esophageal squamous cell carcinomas

“…Important serum peptides to detect the early‐stage ESCC include the combination of alpha 2‐HS glycoprotein (AHSG), thrombospondin 1 (TSP1), and fibrinogen alpha chain (FGA) model. Jia et al applied a high‐throughput serum peptidome analysis in complex serum samples, collected from 477 cancer patients and healthy controls to identify circulating peptide markers in ESCC. A genetic algorithm model containing three significant differentially expressed peptides was established.…”

“…Increased tissue and serum levels of TSP1 in ESCC were verified and correlated with disease progression. Nonetheless, a larger cohort will be required for further unequivocal validation of their clinical application . Tong et al described the plasma POU class 3 homeobox 3 (POU3F3) in combination with serpin family B member 3 (SCCA) protein as an efficient biomarker for the early detection of ESCC.…”

Quantitative proteomic analyses in blood: A window to human health and disease

“…In another study, MALDI‐TOF‐MS was used to analyze 477 serum samples from esophageal squamous cell carcinoma (ESCC) patients and 3 diagnostic peptides were identified. They developed a genetic algorithm model that demonstrated a superior diagnostic performance for early stage ESCC patients compared with other well‐studied proteins . Proteomics studies can also be used to screen for protein molecules associated with disease susceptibility in samples with the same genetic background to explore the mechanisms of disease.…”

“…They developed a genetic algorithm model that demonstrated a superior diagnostic performance for early stage ESCC patients compared with other well-studied proteins. 16 Proteomics studies can also be used to screen for protein molecules associated with disease susceptibility in samples with the same genetic background to explore the mechanisms of disease. In a recent study, proteins related to hepatocellular carcinoma metastasis were investigated in two hepatocellular carcinoma cell lines with the same genetic background but different metastatic potential.…”

Anaphylatoxin C3a: A potential biomarker for esophageal cancer diagnosis

“…Recently, the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MOLDI-TOF-MS) and surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) techniques have been widely employed in the search for cancer biomarkers in brain cancer (12), oral squamous cell carcinoma (13), pancreatic cancer (14), lung cancer (15), esophageal squamous cell carcinoma (16) and breast cancer (17,18), among others. There have been several attempts to identify esophageal carcinoma biomarkers using these techniques (16,(19)(20)(21)(22). However, those studies failed to identify any single biomarker for the diagnosis of esophageal cancer, but rather indicated several proteins.…”