Background Esophageal adenocarcinoma (EAC) is a highly aggressive cancer with poor prognosis, often arising from gastroesophageal reflux disease (GERD) and its precursor, Barrett’s esophagus (BE). Although only a small proportion of individuals with GERD or BE develop EAC, accurately identifying those at high risk is critical for early intervention. Current surveillance methods, such as endoscopy, are invasive and have limited accuracy in predicting malignant transformation. Mass-spectrometry-based proteomics offers a promising alternative by identifying protein biomarkers associated with disease progression.

Method This study evaluated an eight-protein panel in predicting the risk of progression from BE to BE with high-grade dysplasia or EAC, potentially improving early detection and patient outcomes. A cohort of 107 subjects diagnosed with BE was recruited, and biological samples (tissue biopsies) were collected and labeled by a pathologist. Proteomic analysis was conducted using mass spectrometry to profile protein expression across the samples. A statistical test (t-test) was applied to assess differences in the proteomic panel across BE that progressed on follow-up compared to BE without progression.

Results The t-test results revealed significant differences in protein expression levels between subjects with BE who progressed to cancer and those who did not. Key proteins, including CNDP2_TVF, DAD1 (detected via the FLE and ADF peptides), and GPI_LQQ, demonstrated strong statistical significance (p < 0.001) for under-expression, suggesting their potential as early biomarkers for identifying individuals at high risk. S100p_YSG also showed meaningful under-expression (p = 0.0111), indicating its relevance in cancer progression pathways. In contrast, LTF_DGA was over-expressed (p = 0.0226), possibly serving as an activator in the progression pathway and offering a novel therapeutic target.

Conclusions This study identified promising biomarkers on the panel—including CNDP2_TVF, DAD1 (detected via the FLE and ADF peptides), and GPI_LQQ—associated with the development of advanced cancer in BE. Their under-expression could inform novel diagnostic and therapeutic approaches. Integrating these protein profiles with genetic and epigenetic data may provide a more complete understanding of disease progression. Longitudinal studies tracking protein levels over time may also reveal their potential as early cancer markers.

The authors have declared no competing interest.

This study did not receive any funding

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Mayo Clinic IRB irbe@mayo.edu IRB Application #: 23-000689 IRB Approval Date: 3/9/2023 Christopher Hartley Makala Amundson Andrew Cannon Catherine Hagen Christopher Hartley Priyadharshini Sivasubramaniam

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All data produced in the present study are available upon reasonable request to the authors