# Development and validation of predictive models combining cell-Free DNA motifs and protein biomarkers for early detection of esophageal squamous cell carcinoma and precancerous lesion

## TL;DR

Researchers developed a non-invasive test combining DNA and protein markers to detect early signs of esophageal cancer and precancerous lesions.

## Contribution

A novel multi-omics model combining cfDNA motifs and protein biomarkers for early detection of ESCC and precancerous lesions.

## Key findings

- The combined motif-protein model achieved 88.5% sensitivity and 75.4% specificity for detecting ESCC and precancerous lesions.
- The model successfully identified 90.9% of high-grade intraepithelial neoplasia cases and 86.8% of early-stage ESCC cases.
- The model outperformed individual motif and protein models with an area under the curve of 0.90.

## Abstract

Detecting and treating precancerous lesions can lower the incidence of esophageal squamous cell carcinoma (ESCC), making it a key preventive strategy. Although endoscopic screening and intervention can significantly reduce mortality associated with ESCC, they have certain shortcomings. We aimed to develop three predictive models: the motif, eight-protein, and combined motif-protein models to identify ESCC and its precancerous lesions.

Plasma samples were collected for cfDNA sequencing, and nine commonly used clinical protein biomarkers related to the digestive system were measured. Using a total cohort of 199 patients with ESCC, 91 patients with esophageal squamous precancerous lesions (ESPL), and 201 controls, we developed an integrative model based on selected multi-omics biomarkers.

The motif-protein model, integrating 20 principal components of cfDNA terminal motifs with six protein features, outperformed both the motif model and the eight-protein model in distinguishing patients with ESCC and ESPL (area under the curve = 0·90). It achieved an overall sensitivity of 88·5% and a specificity of 75·4%. Notably, it successfully identified 90·9% of high-grade intraepithelial neoplasia cases, 86·8% of stage I ESCC cases, and 87·8% of HGIN or T1aN0 stage ESCC (subset of Stage I) cases who were eligible for endoscopic treatment, highlighting its potential as an effective tool for early diagnosis.

The motif-protein model may serve as an effective tool for the early diagnosis of esophageal lesions. Our findings underscore the clinical potential of the multi-omics liquid biopsy test as a non-invasive method for detecting early esophageal lesions.

The online version contains supplementary material available at 10.1186/s40364-025-00840-9.