Novel Serum Biomarker Investigated for Early Gastric Cancer Diagnosis

Gastric cancer (GC) is one of the most common causes of cancer-related death worldwide. More importantly, most reported GC cases are in developing countries. The high mortality of GC is often due to its nonspecific symptoms and delayed diagnosis.

Early detection is key step in the management of patients and survival improvement. Gastric endoscopy is widely used for GC screening. Magnifying endoscopy (ME) with narrow band imaging (ME-NBI) is also an effective tool for real-time endoscopic diagnosis of early gastric cancer (EGC). However, using these tools, identifying subtle lesions or differentiation between inflammation and early intraepithelial neoplasia is still challenging.


Gastroenterologists at the Shanghai General Hospital (Shanghai, China) enrolled a total of 108 patients who presented with GC between July 2016 and June 2018. The subjects included 38 cases of EGC and 70 cases of advanced gastric cancer (AGC). Also included were 28 patients with low-grade intraepithelial neoplasia (LGN, precancerous group), 37 patients with chronic superficial gastritis (CSG) associated with Helicobacter pylori infection (Hpi), 49 patients with other system malignant tumors (OST) and 178 healthy volunteers (healthy control, HC).

Serum samples from 20 patients with EGC and 20 HCs were selected for polypeptide analysis via mass spectrometry. A nanoliter flow HPLC system, EASY-nLC 1000, with a trap column and a C18 column was used in this study and the analysis was performed using the Orbitrap Elite system (Thermo Scientific, Waltham, MA, USA). To confirm the mass spectrometry results, serum samples from 16 patients with EGC, 16 patients with AGC, and 16 HCs were subjected to immunoblotting against inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4).

The tumor tissues of 20 patients with GC and their adjacent normal tissues were embedded, sectioned, and placed in Leica Bond-Max automatic immunohistochemical machine (Leica Microsystems, Berlin, Germany). The expression profiles of ITIH4 in 312 serum samples, including 26 EGC, 48 AGC, 26 LGN, 37 Hpi, 49 OST, and 126 HC serum samples, were determined using enzyme-linked immunosorbent assay (ELISA, R&D Systems, Minneapolis, MN, USA). To determine the expression levels of target molecules in blood, exosomes in serum samples were isolated, identified, and analyzed.

The investigators reported that ITIH4 was identified as a key biomarker in patients with EGC. Its expression level in serum from the EGC group, which showed the highest specificity (94.5%), was significantly higher than those in sera from other GC groups as well as the control. Western blot analysis, immunohistochemical staining, and exosome analysis also confirmed ITIH4 expression in sera from patients with GC, but not in those from healthy individual.

The authors concluded that the serum ITIH4 expression level is a promising biomarker for the early diagnosis of GC. ITIH4 levels in serum samples from patients at the early stage of GC were significantly higher than those in serum samples from patients with GC at the advanced stage or HCs. This finding indicated that serum ITIH4 levels can be a potential biomarker for early stage GC diagnosis. The study was published on October 20, 2021 on the journal Clinica Chimica Acta.

Related Links:
Shanghai General Hospital
Thermo Scientific
Leica Microsystems
R&D Systems