Abstract
BackgroundEarly diagnosis of esophageal squamous cell carcinoma (ESCC) remains a challenge due to the lack of specific blood biomarkers. We aimed to develop a serum multi-protein signature for the early detection of ESCC.MethodsWe selected 70 healthy controls, 30 precancerous patients, 60 stage I patients, 70 stage II patients and 70 stage III/IV ESCC patients from a completed ESCC case-control study in a high-risk area of China. Olink Multiplex Oncology II targeted proteomics panel was used to simultaneously detect the levels of 92 cancer-related proteins in serum using proximity extension assay.ResultsWe found that 10 upregulated and 13 downregulated protein biomarkers in serum could distinguish the early-stage ESCC from healthy controls, which were validated by the significant dose-response relationships with ESCC pathological progression. Applying least absolute shrinkage and selection operator (LASSO) regression and backward elimination algorithm, ANXA1 (annexin A1), hK8 (kallikrein-8), hK14 (kallikrein-14), VIM (vimentin), and RSPO3 (R-spondin-3) were kept in the final model to discriminate early ESCC cases from healthy controls with an area under curve (AUC) of 0.936 (95% confidence interval: 0.899 ~ 0.973). The average accuracy rates of the five-protein classifier were 0.861 and 0.825 in training and test data by five-fold cross-validation.ConclusionsOur study suggested that a combination of ANXA1, hK8, hK14, VIM and RSPO3 serum proteins could be considered as a potential tool for screening and early diagnosis of ESCC, especially with the establishment of a three-level hierarchical screening strategy for ESCC control.
Highlights
Diagnosis of esophageal squamous cell carcinoma (ESCC) remains a challenge due to the lack of specific blood biomarkers
The government-sponsored endoscopic screening program is conducted for asymptomatic adults in high incidence area for esophageal cancer in China, but the ongoing program introduced a large burden for public health: only a small part of residents could participate in the gastroscopy screening program and even among this small proportion of population long-term follow-up for high-risk subjects is becoming increasingly burdensome as regards endoscopic management [6]
Few effective biomarkers for screening early ESCC are established in clinical applications, because the area under curve (AUC) of most potential biomarkers is usually lower than 80% [8, 13]
Summary
Diagnosis of esophageal squamous cell carcinoma (ESCC) remains a challenge due to the lack of specific blood biomarkers. The government-sponsored endoscopic screening program is conducted for asymptomatic adults in high incidence area for esophageal cancer in China, but the ongoing program introduced a large burden for public health: only a small part of residents could participate in the gastroscopy screening program and even among this small proportion of population long-term follow-up for high-risk subjects is becoming increasingly burdensome as regards endoscopic management [6]. Esophageal squamous cell carcinoma (ESCC) is the dominant histological subtype of esophageal cancer (> 80% proportion), especially in Asia and Eastern African, [12] showing contrasting risk factors and molecular features with esophageal adenocarcinoma. Few effective biomarkers for screening early ESCC are established in clinical applications, because the area under curve (AUC) of most potential biomarkers is usually lower than 80% [8, 13]
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