For early gastrointestinal lesions, size is an important factor in the selection of treatment. Virtual scale endoscope (VSE) is a newly developed endoscope that can measure size more accurately than visual measurement. This study aimed to investigate whether VSE measurement is accurate for early gastrointestinal lesions of various sizes and morphologies.

This study prospectively enrolled patients with early gastrointestinal lesions ≤20 mm in size visually. Lesion sizes were measured in the gastrointestinal tract visually, on endoscopic resection specimens with VSE, and finally on endoscopic resection specimens using a ruler. The primary endpoint was the normalized difference (ND) of VSE measurement. The secondary endpoints were the ND of visual measurement and the variation between NDs of VSE and visual measurements. ND was calculated as (100 × [measured size - true size] / true size) (%). True size was defined as size measured using a ruler.

This study included 60 lesions from April 2022 to December 2022, with 20 each in the esophagus, stomach, and colon. The lesion size was 14.0 ± 6.3 mm (mean ± standard deviation). Morphologies were protruded, slightly elevated, and flat or slightly depressed type in 8, 24, and 28 lesions, respectively. The primary endpoint was 0.3 ± 8.8%. In the secondary endpoints, the ND of visual measurement was -1.7 ± 29.3%, and the variability was significantly smaller in the ND of VSE measurement than in that of visual measurement (p < 0.001, F-test).

VSE measurement is accurate for early gastrointestinal lesions of various sizes and morphologies.

A computer-aided detection (CAD) system for early esophagus carcinoma identification during endoscopy with narrow-band imaging (NBI) was evaluated in a large-scale, prospective, tandem, randomized controlled trial to assess its effectiveness. The study was registered at the Chinese Clinical Trial Registry (ChiCTR2100050654, 2021/09/01). Involving 3400 patients were randomly assigned to either routine (routine-first) or CAD-assisted (CAD-first) NBI endoscopy, followed by the other procedure, with targeted biopsies taken at the end of the second examination. The primary outcome was the diagnosis of 1 or more neoplastic lesion of esophagus during the first examination. The CAD-first group demonstrated a significantly higher neoplastic lesion detection rate (3.12%) compared to the routine-first group (1.59%) with a relative detection ratio of 1.96 (P = 0.0047). Subgroup analysis revealed a higher detection rate in junior endoscopists using CAD-first, while no significant difference was observed for senior endoscopists. The CAD system significantly improved esophageal neoplasm detection, particularly benefiting junior endoscopists.

Endoscopic submucosal dissection (ESD) is a crucial yet challenging multi-phase procedure for treating early gastrointestinal cancers. This study developed an artificial intelligence (AI)-based automated surgical workflow recognition model for esophageal ESD and proposed an innovative training program based on esophageal ESD videos with or without AI labels to evaluate its effectiveness for trainees.

We retrospectively analyzed complete ESD videos collected from seven hospitals worldwide between 2016 and 2024. The ESD surgical workflow was divided into 6 phases and these videos were divided into five datasets for AI model. Trainees were invited to participate in this multimedia training program and were assigned to the AI or control group randomly. The performance of the AI model and label testing were evaluated using the accuracy.

A total of 195 ESD videos (782,488 s, 9268 phases) were included. The AI model achieved accuracy of 92.08% (95% confidence interval (CI), 91.40-92.76%), 91.71% (95% CI 90.11-93.31%), and 89.84% (95% CI 87.42-92.25%) in the training, internal, and external test dataset (esophagus), respectively. It also achieved acceptable results in the external test dataset (stomach, colorectum). For the training program, the overall label testing accuracy of the AI group learning ESD videos with AI labels was 88.73 ± 2.97%, significantly higher than the control group without AI labels (81.51 ± 4.63%, P < 0.001).

The AI model achieved high accuracy in the large ESD video datasets. The training program improves understanding of the complexity of ESD workflow and demonstrates the program's effectiveness for trainees.

The resection of large superficial esophageal neoplastic lesions (SENLs) presents significant challenges for traditional endoscopic submucosal dissection (ESD). Endoscopic submucosal tunnel dissection (ESTD) has emerged as an alternative that potentially reduces resection difficulty.

We aimed to compare ESTD and ESD in the treatment of large SENLs.

Meta-analysis of randomized controlled trials (RCTs).

We systematically searched MEDLINE, EMBASE, Cochrane Library, and Wanfang Data for RCTs comparing ESTD with ESD for large SENLs until July 1, 2024. The grading of recommendations assessment, development, and evaluation framework was used to assess the certainty of the evidence, whereas trial sequential analysis (TSA) was used to control for random errors and evaluate conclusion validity.

Four RCTs involving 315 patients were included. The pooled analysis showed that ESTD was significantly faster than ESD (mean differences 5.06, 95% confidence interval: 3.31-6.80; p < 0.01; I 2 = 0%; low certainty of evidence). TSA indicated a desired sample size of 162, with the cumulative Z curve crossing the trial sequential monitoring boundary. ESTD also had lower rates of major complications and post-operation esophageal stricture (low certainty of evidence). No significant differences were found in en bloc and curative resection rates.

With low certainty, ESTD appears superior to ESD for large SENLs, offering faster resection and fewer complications, with similar en bloc and curative resection rates.

This meta-analysis protocol was registered on PROSPERO (CRD42024520754).

Patients diagnosed with pathologic T1N0 esophageal squamous cell carcinoma and treated with surgery alone have a good prognosis and are generally followed up without adjuvant therapy. However, recurrence has been observed in this patient group. Therefore, this study aimed to identify recurrence and prognostic factors in patients with pathologic T1N0 esophageal squamous cell carcinoma who were treated with surgery alone.

Of the 532 patients who underwent esophagectomy with R0 resection at Hiroshima University Hospital between August 2003 and November 2018, 124 who underwent only esophagectomy and had pathological T1N0 esophageal squamous cell carcinoma were included in the study. Recurrence and prognostic factors were analyzed and details of recurrence were evaluated.

The 5-year recurrence-free survival and 5-year overall survival rates were 84.7% and 87.2%, respectively. Recurrence was observed in 12 (9.7%) patients. Univariate and multivariate analyses showed that the histologic type (poorly differentiated compared with others) and lymphatic and/or vascular invasion (positive compared with negative) were statistically significant for recurrence-free survival. Kaplan-Meier curves for recurrence-free survival and overall survival showed that prognosis was significantly stratified according to these factors. All patients with poorly differentiated and positive lymphatic and/or vascular invasion experienced recurrence and recurrence pattern is all distant metastases.

Poorly differentiated and lymphatic and/or vascular invasion are important recurrence and prognostic predictors in pathologic T1N0 esophageal squamous cell carcinoma treated with surgery alone. Patients with these prognostic factors experienced increased recurrence rates, often with distant metastasis. Therefore, adjuvant therapy may be beneficial for such patients and follow-ups should be performed at closer intervals.

Cancers of the digestive system are major contributors to global cancer-associated morbidity and mortality, accounting for 35% of annual cases of cancer deaths. The etiologies, molecular features, and therapeutic management of these cancer entities are highly heterogeneous and complex. Over the last decade, genomic and functional studies have provided unprecedented insights into the biology of digestive cancers, identifying genetic drivers of tumor progression and key interaction points of tumor cells with the immune system. This knowledge is continuously translated into novel treatment concepts and targets, which are dynamically reshaping the therapeutic landscape of these tumors. In this review, we provide a concise overview of the etiology and molecular pathology of the six most common cancers of the digestive system, including esophageal, gastric, biliary tract, pancreatic, hepatocellular, and colorectal cancers. We comprehensively describe the current stage-dependent pharmacological management of these malignancies, including chemo-, targeted, and immunotherapy. For each cancer entity, we provide an overview of recent therapeutic advancements and research progress. Finally, we describe how novel insights into tumor heterogeneity and immune evasion deepen our understanding of therapy resistance and provide an outlook on innovative therapeutic strategies that will shape the future management of digestive cancers, including CAR-T cell therapy, novel antibody-drug conjugates and targeted therapies.

The aim of the present study was to investigate the relationship between the cellular ecosystem and the progression of esophageal carcinoma (ESCA) based on the evolution of macrophages and to analyze the potential of using macrophages as a new therapeutic approach in ESCA treatment.

Macrophage-based immunotherapy could be used for treating ESCA patients, but its clinical application is limited by the intra-tumor heterogeneity of macrophages.

The objective of this study was to analyze the diversity, differentiation trajectory, and intercellular communication of macrophages in ESCA and its prognostic significance.

Single-cell RNA sequencing (scRNA-seq) data in the GSE154763 dataset were downloaded from Gene Expression Omnibus (GEO) to identify cell clusters and annotate cell types using the Seurat R package. The scRNA-seq profiles of macrophages were extracted, and cluster analysis was performed to identify macrophage subsets. The differentiation trajectories of macrophage subgroups were visualized employing Monocle2. Finally, ligand-receptor pairs and communication intensity among the classified subgroups were analyzed using Cell Chat.

A total of 8 cell types were identified between ESCA tissues and paracancer tissues. The most abundant macrophages in ESCA tissues were further divided into 5 cell clusters. Compared with the normal tissues, the proportion of HSPA6+ macrophages in ESCA tissues increased the most, and the number of ligand-receptor pairs that mediated the communication of HSPA6+ macrophages with mast cells and monocytes also increased significantly. More importantly, a high proportion of HSPA6+ macrophages was inversely correlated with the survival outcomes for ESCA patients.

This study analyzed the diversity, distribution and differentiation trajectory of macrophages in ESCA tissues at single-cell level and classified a prognostic macrophage subtype (HSPA6+ macrophages) of ESCA, providing a theoretical basis for macrophage-targeted therapy in ESCA.

Circular RNA (circRNA) plays a significant role in esophagus squamous cell carcinoma (ESCC) progression. Nevertheless, circ-TTC17 roles in ESCC have not fully understood.

The levels of circ-TTC17, miR-145-5p and sirtuin 1 (SIRT1) were determined using qRT-PCR. ESCC cell functions were examined by CCK8 assay, flow cytometry, transwell assay and colony formation assay. The relative protein levels of autophagy marker and SIRT1 were determined by western blot (WB). The interactions among circ-TTC17, miR-145-5p, and SIRT1 were verified by dual-luciferase reporter assay and RIP assay.

circ-TTC17 was overexpressed and miR-145-5p was underexpressed in ESCC. circ-TTC17 knockdown restrained ESCC cell proliferation and metastasis, while enhance apoptosis and autophagy-mediated radiosensitivity. Circ-TTC17 could sponge miR-145-5p, and its inhibitor reversed the inhibitory effect of circ-TTC17 knockdown on ESCC cell progression. Additionally, SIRT1 was targeted by miR-145-5p, and SIRT1 overexpression abolished miR-145-5p-mediated the suppressive effect on ESCC cell progression. Also, circ-TTC17 interference reduced ESCC tumor growth via miR-145-5p/SIRT1 axis.

circ-TTC17 promoted ESCC cell growth, metastasis and inhibited autophagy-mediated radiosensitivity by miR-145-5p/SIRT1 axis.

Esophageal cancer is one of the common cancers. Risk factors are well recognized and lead most commonly to two distinct histological subtypes (squamous cell carcinoma and adenocarcinoma). The diagnosis is based on endoscopic evaluation. The most challenging aspect of management is accurate staging as it guides appropriate management. Endoscopic ultrasound, computed tomography (CT), positron emission tomography-CT, and magnetic resonance imaging are the imaging tests employed for the staging. Each imaging test has its own merits and demerits. Imaging is also critical to evaluate posttreatment complication and for response assessment. In this review article, we discuss in detail the risk factors, anatomical aspects, and role of imaging test in staging and evaluation of complications and response after treatment.

Esophageal cancer (ECa) is one of the most deadly cancers, with increasing incidence worldwide and poor prognosis. While endoscopy is recommended for the detection of ECa in high-risk individuals, it is not suitable for large-scale screening due to its invasiveness and inconvenience.

In this study, a novel gene methylation panel was developed for a blood-based test, and its diagnostic efficacy was evaluated using a cohort of 304 participants (203 cases, 101 controls). The assessment focused on the DNA methylation levels of SEPTIN9, tissue factor pathway inhibitor 2 (TFPI2), and the fragile histidine triad gene (FHIT) in patients with ECa, benign esophageal disease, and healthy controls. The receiver operating characteristic (ROC) curve was generated for the panel to calculate the area under the curve (AUC), sensitivity, specificity, and 95% confidence intervals (CIs), along with a comparison to the gold standard of pathological examination. The consistency between biomarker and pathological diagnosis was evaluated with kappa analysis conducted with IBM SPSS Statistics. The Chi-square test or Fisher's exact test was utilized to assess the association of test positivity with demographic characteristics.

In patients with ECa, SEPTIN9, TFPI2, and FHIT DNA methylation levels were significantly higher compared to those with benign esophageal disease or healthy controls. The panel demonstrated promising potential as a noninvasive tool for distinguishing malignant tumors from both healthy controls and benign esophageal diseases, achieving an area under the ROC curve of 0.925 (95% CI: 0.889-0.952), with a sensitivity of 79.8% [95% CI 73.6-85.1%] and specificity of 95.0% [95% CI 88.8-98.4%]. In particular, the panel showed exceptional diagnostic efficiency for stage 0, I, and II cancer patients with sensitivity at 69.0, 75.5%, and 78.9%, respectively. The comparison revealed a Kappa value of 0.725 between RT-PCR testing and the established gold standard of pathological examination, indicating a high level of consistency. Additionally, there was no bias in diagnostic efficiency based on age, gender, or the presence of other malignancies (non-esophageal cancers).

The study's findings suggested that the DNA methylation biomarkers panel holds promise as a non-invasive and convenient diagnostic test for ECa. The panel's ability to distinguish malignant tumors from benign esophageal diseases, coupled with its high sensitivity and specificity, presented opportunities to enhance the over-all diagnosis of high-risk population when in conjunction with existing detection methods.

Esophageal squamous cell carcinoma (ESCC) remains a significant global health challenge, being the sixth leading cause of cancer mortality with pronounced geographic variability. The incidence rates range from 125 per 100,000 in northern China to 1-1.5 per 100,000 in the United States, driven by environmental and lifestyle factors such as tobacco and alcohol use, dietary habits, and pollution. Major modifiable risk factors include tobacco and alcohol consumption, with a synergistic risk increase when combined. Nonmodifiable risk factors include previous diagnoses of head and neck squamous cell carcinoma (H&N SCC), achalasia, and prior radiotherapy. Prevention strategies must be tailored to specific regional burdens to efficiently allocate medical and financial resources. Gastrointestinal endoscopy is crucial in reducing ESCC burden through early detection and characterization of neoplastic changes, such as high-grade dysplasia. Early diagnosis significantly improves survival rates, while endoscopic resection of noninvasive dysplasia can prevent ESCC onset, reducing treatment burden for advanced disease. Postresection surveillance can detect high-risk metachronous lesions. Despite these benefits, endoscopic prevention faces challenges, including the lack of high-level evidence supporting its efficacy, opportunity costs, the need for specialized training and techniques, and the requirement for advanced technology investments. This Position Statement from the World Endoscopy Organization (WEO) aims to address these challenges, supplying recommendations for the exploitation of endoscopic resources regarding the possible role of screening, quality, and training for the detection, characterization, resection, and surveillance of ESCC.

The burden of esophageal cancer varies across different regions of the world. The aim of this study is to analyze the current burden of esophageal cancer in 185 countries in 2022 and to project the trends up to the year 2050.

We extracted data on primary esophageal cancer cases and deaths from the GLOBOCAN 2022 database, which includes data from 185 countries. Age-standardized incidence rates (ASIR) and mortality rates (ASMR) per 100,000 person-years were calculated by stratifying by Human Development Index (HDI) levels and regions. Considering changes in population size and age structure, we assumed that the risks of incidence and mortality remain constant at the levels of 2022 to forecast the number of new cases and deaths from esophageal cancer globally by 2050.

In 2022, an estimated 511,054 people were diagnosed with esophageal cancer globally, and 445,391 died from the disease. The global ASIR and ASMR for esophageal cancer were 5.00 and 4.30 per 100,000, respectively. The highest rates were observed in East Africa (7.60 for incidence, 7.20 for mortality per 100,000), East Asia (7.60 for incidence, 5.90 for mortality per 100,000), Southern Africa (6.30 for incidence, 5.90 for mortality per 100,000), and South Central Asia (5.80 for incidence, 5.50 for mortality per 100,000). Among the 185 countries worldwide, esophageal cancer was among the top five causes of cancer incidence in 18 countries and among the top five causes of cancer mortality in 25 countries. In 2022, China had 224,012 new cases and 187,467 deaths from esophageal cancer, accounting for approximately 43.8% and 42.1% of the global total, respectively, which is higher than the proportion of China's population to the global population (17.9%). ASIR was 8.30 per 100,000, and ASMR was 6.70 per 100,000. The highest burden of esophageal cancer was in high HDI countries, with new cases and deaths accounting for 51.3% and 50.0% of the global total, respectively. The ASIR and ASMR were highest in the high HDI group (6.10 and 5.10 per 100,000, respectively), also exceeding the global averages. There was a trend of decreasing mortality to incidence ratio with increasing HDI, but no correlation was observed between HDI and ASIR or ASMR. In all regions worldwide, the incidence and mortality rates were higher in males than in females (with a male-to-female ASR ratio ranging from 1.10 to 28.7). Compared to 2022, it is projected that by 2050, the number of new esophageal cancer cases will increase by approximately 80.5%, and deaths will increase by 85.4% due to population growth and aging.

The burden of esophageal cancer remains heavy. Adopting a healthy lifestyle, including reducing tobacco and alcohol intake, avoiding moldy foods, and increasing intake of fresh fruits and vegetables, can help reduce the risk of stomach and esophageal cancer. In addition, the development and implementation of evidence-based and effective public health policies are critical to reducing the global disease burden of esophageal cancer.

Cisplatin (CDDP) is the primary drug used in the initial treatment of esophageal cancer (EC). However, its side effects and resistance can limit its effectiveness in clinical therapy. Curcumin (Cur)-mediated glutathione (GSH) depletion can reverse resistance, enhance the chemosensitivity of CDDP, and further improve the efficacy of platinum-containing chemotherapy in the treatment of esophageal cancer. However, it is also faced with problems of poor water solubility and low bioavailability in vivo, which severely hinders cancer treatments. In order to address these issues, we developed a novel nanotherapeutic system called CDCZA, combining Cur/CDDP/Cu/ZIF8@Au to enhance chemotherapy through GSH depletion and chemodynamic therapy through self-produced H2O2. Cu and CDDP were precisely co-loaded into Cu/ZIF8 nanoparticles using a one-pot method, then ultra-small gold nanoparticles mimicking glucose oxidase (Au nanoparticles) were embedded in the outer shell to create the CDCZA nano system. The released Cur could notably decrease intracellular GSH content and thus improve the chemosensitivity of CDDP, resulting in severe cellular apoptosis. And the Au nanoparticles effectively enabled chemodynamic therapy enhancement by accelerating the depletion of β-D-glucose into H2O2. As a result, the CDCZA nanoparticles showed increased tumor accumulation and improved antitumor effectiveness in a model of EC. Taken together, this work provides a new idea for the clinical design of efficient treatment reagents for EC.

Esophageal squamous cell carcinoma (ESCC) has a high incidence and mortality rate. Postoperative positive surgical margins (PSM) often correlate with poor prognosis. This study aims to develop and validate a predictive model for PSM positivity in ESCC patients, with the potential to guide preoperative planning and improve patient outcomes.

We conducted a retrospective analysis of 1776 patients who underwent esophageal cancer surgery at the First Affiliated Hospital of Jilin University between January 2015 and December 2023. Patients with visible residual tumors (R2) or microscopic residual tumors (R1) at the surgical margins were classified as having PSM. High-dimensional pathological features were extracted from digital pathological sections using CellProfiler software. The selected features were used to develop a predictive model based on decision trees and generalized linear regression, and the model was validated in an independent cohort. Clinically significant pathological factors (P < 0.05) were included in multivariate logistic regression for further validation. The model's performance was assessed using calibration curves and receiver operating characteristic (ROC) curves, generated with the Bootstrap method. Decision curve analysis (DCA) was employed to evaluate the clinical utility of the predictive model.

A total of 229 patients (12.89%) were diagnosed with PSM. Logistic regression analysis identified multifocal lesions, vascular invasion, and pathomics-based features as independent predictors of PSM. The predictive model, represented by a decision tree, demonstrated good discrimination with an area under the ROC curve of 0.899 (95% CI: 0.842-0.956, P < 0.001), and a strong calibration curve between the predicted probability and the actual probability. Additionally, the nomogram demonstrated slightly inferior discrimination with an area under the ROC curve of 0.803 (95% CI: 0.734-0.872, P < 0.001) in the training cohort.

Our study successfully established and validated a pathology-based predictive model for PSM risk, which could enhance preoperative evaluation and inform treatment strategies for ESCC.

The early detection of esophageal cancer is crucial to enhancing patient survival rates, and endoscopy remains the gold standard for identifying esophageal neoplasms. Despite this fact, accurately diagnosing superficial esophageal neoplasms poses a challenge, even for seasoned endoscopists. Recent advancements in computer-aided diagnostic systems, empowered by artificial intelligence (AI), have shown promising results in elevating the diagnostic precision for early-stage esophageal cancer.

In this study, we expanded upon traditional red-green-blue (RGB) imaging by integrating the YOLO neural network algorithm with hyperspectral imaging (HSI) to evaluate the diagnostic efficacy of this innovative AI system for superficial esophageal neoplasms. A total of 1836 endoscopic images were utilized for model training, which included 858 white-light imaging (WLI) and 978 narrow-band imaging (NBI) samples. These images were categorized into three groups, namely, normal esophagus, esophageal squamous dysplasia, and esophageal squamous cell carcinoma (SCC).

An additional set comprising 257 WLI and 267 NBI images served as the validation dataset to assess diagnostic accuracy. Within the RGB dataset, the diagnostic accuracies of the WLI and NBI systems for classifying images into normal, dysplasia, and SCC categories were 0.83 and 0.82, respectively. Conversely, the HSI dataset yielded higher diagnostic accuracies for the WLI and NBI systems, with scores of 0.90 and 0.89, respectively.

The HSI dataset outperformed the RGB dataset, demonstrating an overall diagnostic accuracy improvement of 8%. Our findings underscored the advantageous impact of incorporating the HSI dataset in model training. Furthermore, the application of HSI in AI-driven image recognition algorithms significantly enhanced the diagnostic accuracy for early esophageal cancer.

This study aimed to develop a predictive model utilizing radiomics and body composition features derived from 18F-FDG PET/CT scans to forecast progression-free survival (PFS) and overall survival (OS) outcomes in patients with esophageal squamous cell carcinoma (ESCC).

We analyzed data from 91 patients who underwent baseline 18F-FDG PET/CT imaging. Radiomic features extracted from PET and CT images and subsequent radiomics scores (Rad-scores) were calculated. Body composition metrics were also quantified, including muscle and fat distribution at the L3 level from CT scans. Multiparametric survival models were constructed using Cox regression analysis, and their performance was assessed using the area under the time-dependent receiver operating characteristic (ROC) curve (AUC) and concordance index (C-index).

Multivariate analysis identified Rad-scorePFS (P = 0.003), sarcopenia (P < 0.001), and visceral adipose tissue index (VATI) (P < 0.001) as independent predictors of PFS. For OS, Rad-scoreOS (P = 0.001), sarcopenia (P = 0.002), VATI (P = 0.037), stage (P = 0.042), and body mass index (BMI) (P = 0.008) were confirmed as independent prognostic factors. Integration of the Rad-score with clinical variables and body composition parameters enhanced predictive accuracy, yielding C-indices of 0.810 (95% CI: 0.737-0.884) for PFS and 0.806 (95% CI: 0.720-0.891) for OS.

This study underscored the potential of combining Rad-score with clinical and body composition data to refine prognostic assessment in ESCC patients.

Liquid biopsy technology provides invaluable support for the early diagnosis of tumors and surveillance of disease course by detecting tumor-related biomarkers in bodily fluids. Currently, liquid biopsy techniques are mainly divided into two categories: biomarker and label-free. Biomarker liquid biopsy techniques utilize specific antibodies or probes to identify and isolate target cells, exosomes, or molecules, and these techniques are widely used in clinical practice. However, they have certain limitations including dependence on tumor markers, alterations in cell biological properties, and high cost. In contrast, label-free liquid biopsy techniques directly utilize physical or chemical properties of cells, exosomes, or molecules for detection and isolation. These techniques have the advantage of not needing labeling, not impacting downstream analysis, and low detection cost. However, most are still in the research stage and not yet mature. This review first discusses recent advances in liquid biopsy techniques for early tumor diagnosis and disease surveillance. Several current techniques are described in detail. These techniques exploit differences in biomarkers, size, density, deformability, electrical properties, and chemical composition in tumor components to achieve highly sensitive tumor component identification and separation. Finally, the current research progress is summarized and the future research directions of the field are discussed.

Esophageal squamous cell carcinoma (ESCC) is the most common histological type of esophageal cancer with a poor prognosis. Early diagnosis and prognosis assessment are crucial for improving the survival rate of ESCC patients. With the advancement of artificial intelligence (AI) technology and the proliferation of medical digital information, AI has demonstrated promising sensitivity and accuracy in assisting precise detection, treatment decision-making, and prognosis assessment of ESCC. It has become a unique opportunity to enhance comprehensive clinical management of ESCC in the era of precision oncology. This review examines how AI is applied to the diagnosis, treatment, and prognosis assessment of ESCC in the era of precision oncology, and analyzes the challenges and potential opportunities that AI faces in clinical translation. Through insights into future prospects, it is hoped that this review will contribute to the real-world application of AI in future clinical settings, ultimately alleviating the disease burden caused by ESCC.

Submucosal infiltration of less than 200 μm is considered an indication for endoscopic surgery in cases of superficial esophageal cancer and precancerous lesions. This study aims to identify the risk factors associated with submucosal infiltration exceeding 200 micrometers in early esophageal cancer and precancerous lesions, as well as to establish and validate an accompanying predictive model.

Risk factors were identified through least absolute shrinkage and selection operator (LASSO) and multivariate logistic regression. Various machine learning (ML) classification models were tested to develop and evaluate the most effective predictive model, with Shapley Additive Explanations (SHAP) employed for model visualization.

Predictive factors for early esophageal invasion into the submucosa included endoscopic ultrasonography or magnifying endoscopy> SM1(P<0.001,OR = 3.972,95%CI 2.161-7.478), esophageal wall thickening(P<0.001,OR = 12.924,95%CI,5.299-33.96), intake of pickled foods(P=0.04,OR = 1.837,95%CI,1.03-3.307), platelet-lymphocyte ratio(P<0.001,OR = 0.284,95%CI,0.137-0.556), tumor size(P<0.027,OR = 2.369,95%CI,1.128-5.267), the percentage of circumferential mucosal defect(P<0.001,OR = 5.286,95%CI,2.671-10.723), and preoperative pathological type(P<0.001,OR = 4.079,95%CI,2.254-7.476). The logistic regression model constructed from the identified risk factors was found to be the optimal model, demonstrating high efficacy with an area under the curve (AUC) of 0.922 in the training set, 0.899 in the validation set, and 0.850 in the test set.

A logistic regression model complemented by SHAP visualizations effectively identifies early esophageal cancer reaching 200 micrometers into the submucosa.

SYT13 is one of the atypical members of the synaptotagmin (SYT) family whose function has attracted considerable attention in recent years. Although SYT13 has been studied in several types of human cancers, such as lung cancer, its role in esophageal squamous cell carcinoma (ESCC) is still unclear. It was demonstrated that SYT13 is significantly upregulated in ESCC tissues compared with normal ones and correlated with higher degree of malignancy. Knockdown of SYT13 could inhibit ESCC cell proliferation and migration, while promoting cell apoptosis. Meanwhile, ESCC cells with relatively lower SYT13 expression grew slower in vivo and finally formed smaller xenografts. Furthermore, acrosomal vesicular protein 1 was identified as a potential downstream target of SYT13, which regulates cell phenotypes of ESCC cells in cooperation with SYT13. All the in vitro and in vivo results in this study identified that SYT13 silencing could be an effective strategy to inhibit the development of ESCC, which could be considered as a promising therapeutic target in the treatment of ESCC.

Early detection of cancer remains an unmet need in clinical practice, and high diagnostic sensitivity and specificity biomarkers are urgently required. Here, we attempted to identify secreted proteins encoded by super-enhancer (SE)-driven genes as diagnostic biomarkers for esophageal squamous cell carcinoma (ESCC).

We conducted an integrative analysis of multiple data sets including ChIP-seq data, secretome data, CCLE data and GEO data to screen secreted proteins encoded by SE-driven genes. Using ELISA, we further identified up-regulated secreted proteins through a small size of clinical samples and verified in a multi-centre validation stage (345 in test cohort and 231 in validation cohort). Receiver operating characteristic curves were used to calculate diagnostic accuracy. Artificial intelligence (AI) method named gradient boosting machine (GBM) were applied for model construction to enhance diagnostic accuracy.

Serum EFNA1 and MMP13 were identified, and showed significantly higher levels in ESCC patients compared to normal controls. An integrated Five-Biomarker Panel (iFBPanel) established by combining EFNA1, MMP13, carcino-embryonic antigen, Cyfra21-1 and squmaous cell carcinoma antigen had AUCs of 0.881 and 0.880 for ESCC in test and validation cohorts, respectively. Importantly, the iFBPanel also exhibited good performance in detecting early-stage ESCC patients (0.872 and 0.864). Furthermore, the iFBPanel was further empowered by AI technology which showed excellent diagnostic performance in early-stage ESCC (0.927 and 0.907).

Our study suggested that serum EFNA1 and MMP13 could potentially assist ESCC detection, and provided an easy-to-use detection model that might help the diagnosis of early-stage ESCC.

The application of liquid biopsy analysis utilizing circulating tumor DNA (ctDNA) has gained prominence as a biomarker in specific cancer types. Nevertheless, the correlation between ctDNA and the prognostic outcomes of patients with esophageal cancer (EC) remains a subject of controversy. This meta-analysis aims to assess the correlation between ctDNA and the prognosis of EC patients.

The authors systematically explored Embase, PubMed, and the Cochrane Database to identify studies reporting on the prognostic value of ctDNA in EC patients before November 2023. The primary outcome involved the determine of associations between ctDNA with overall survival (OS), disease-free survival (DFS)/recurrence-free survival (RFS), as well asprogression-free survival (PFS) among EC patients. Secondary outcomes encompassed a detailed subgroup analysis in the setting of EC, including parameters such as detection time, histological subtypes, treatment modalities, regions, anatomic locations, and detection methods. Publication bias was assessed utilizing Begg's test, Egger's test, and funnel plots. A sensitivity analysis was conducted by systematically excluding individual studies to evaluate the stability of the results.

A total of 1203 studies were initially screened, from which 13 studies underwent further analysis, encompassing 604 patients diagnosed with EC. The comprehensive pooled analysis indicated a significant association between the detection of ctDNA and poor OS (HR: 3.65; 95% CI: 1.97-6.75, P <0.001), DFS/RFS (HR: 6.08; 95% CI: 1.21-30.50, P <0.001), and PFS (HR: 2.84; 95% CI: 1.94-4.16, P <0.001). Subgroup analysis showed that ctDNA remained a consistent negative predictor of OS when stratified by different detection time, histological subtypes, regions, anatomic locations, and detection methods. Furthermore, subgroup analysis stratified by regions and study types demonstrated an association between ctDNA detection and poor PFS in EC patients.

Our results indicate plasma ctDNA may serve as robust prognostic markers for OS, DFS/RFS, and PFS among EC patients. This finding suggests that plasma ctDNA could offer a highly effective approach for risk stratification and personalized medicine.

Given the significant burden of upper digestive diseases, there has been a substantial increase in the utilization of esophagogastroduodenoscopy (EGD) in China from 2012 to 2019. The objective of this study is to investigate the development, practice, and factors influencing the widespread use of EGD during this period.

Two national censuses were conducted among all hospitals in mainland China that perform gastrointestinal endoscopy. These censuses aimed to extract information on the infrastructure, volume, and quality of EGD. The analysis of potential factors influencing EGD practice was based on real-world data from open access sources.

From 2012 to 2019, the number of hospitals performing EGD in mainland China increased from 1,518 to 2,265 (1.49-fold) in tertiary hospitals and from 3,633 to 4,097 (1.12-fold) in secondary hospitals, respectively. The national utilization rate of EGD also increased from 1,643.53 to 2,018.06 per 100,000 inhabitants, indicating a 1.23-fold increase. Regions with more endoscopists per 100,000 inhabitants (OR 9.61, P<0.001), more tertiary hospitals performing EGD per million inhabitants (OR 2.43, P<0.001), higher incidence of esophageal and gastric cancer (OR 2.09, P=0 016), and higher number of hospitals performing EGD per million inhabitants (OR 1.77, P=0.01) tended to provided more numerous and qualitied EGD. And hospital grading, regional GDP, incidence of esophageal and gastric cancer and the volume of EGD were observed as the significantly relevant factors of malignant dictation rate (MDR) (P<0.05), but not the number and educational background of endoscopists.

Over the past seven years, China has made significant progress in EGD. However, challenges persist in terms of quality and inequality.

Simultaneous profiling of cell-free DNA (cfDNA) methylation and fragmentation features to improve the performance of cfDNA-based cancer detection is technically challenging. We developed a method to comprehensively analyze multimodal cfDNA genomic features for more sensitive esophageal squamous cell carcinoma (ESCC) detection.

Enzymatic conversion-mediated whole-methylome sequencing was applied to plasma cfDNA samples extracted from 168 patients with ESCC and 251 noncancer controls. ESCC characteristic cfDNA methylation, fragmentation, and copy number signatures were analyzed both across the genome and at accessible cis-regulatory DNA elements. To distinguish ESCC from noncancer samples, a first-layer classifier was developed for each feature type, the prediction results of which were incorporated to construct the second-layer ensemble model.

ESCC plasma genome displayed global hypomethylation, altered fragmentation size, and chromosomal copy number alteration. Methylation and fragmentation changes at cancer tissue-specific accessible cis-regulatory DNA elements were also observed in ESCC plasma. By integrating multimodal genomic features for ESCC detection, the ensemble model showed improved performance over individual modalities. In the training cohort with a specificity of 99.2%, the detection sensitivity was 81.0% for all stages and 70.0% for stage 0-II. Consistent performance was observed in the test cohort with a specificity of 98.4%, an all-stage sensitivity of 79.8%, and a stage 0-II sensitivity of 69.0%. The performance of the classifier was associated with the disease stage, irrespective of clinical covariates.

This study comprehensively profiles the epigenomic landscape of ESCC plasma and provides a novel noninvasive and sensitive ESCC detection approach with genome-scale multimodal analysis.

To assess the clinical relevance and prognostic value of changes in the Naples prognostic score (NPS) after neoadjuvant chemoradiotherapy (NACR) among esophageal squamous cell carcinoma (ESCC) patients.

We studied 232 locally advanced ESCC patients who received NACR before undergoing esophagectomy retrospectively. Categorizing individuals into the elevated NPS group and the non-elevated NPS group based on the change in NPS after NACR (ΔNPS > 0 or ∆NPS ≤ 0), we examined and compared the clinicopathological characteristics, survival rates, and postoperative complications between these 2 groups (∆NPS = post-NACR NPS - pre-NACR NPS).

Results: Out of the 232 patients enrolled, 105 exhibited elevated NPS levels, while 127 showed non-elevated NPS levels. Survival analyses indicated inferior overall survival (OS) (p=0.024) and recurrence-free survival (RFS) (p=0.047) in the elevated NPS cohort compared to the non-elevated NPS cohort. Subsequent cox regression analyses identified the post-NACR change in NPS as an independent prognostic indicator for RFS (p=0.029) and OS (p=0.036).

Elevated NPS post-NACR emerged as a significant indicator of worse prognosis for locally advanced ESCC patients who underwent NACR. This finding has great potential to be useful for recognizing high-risk ESCC patients who received NACR before undergoing esophagectomy and making individualized subsequent therapeutic decisions in clinical practice.

Esophageal squamous cell carcinoma stands as a notably aggressive malignancy within the digestive system. In cases of early esophageal cancer without lymph node metastasis, endoscopic surgical resection offers a viable alternative, often resulting in improved patient quality of life. However, the paucity of methods to preoperatively ascertain lymph node involvement complicates surgical planning. SOX4 gene was previously found to be highly associated with invasive metastasis in our work through single-cell RNA sequencing on 5 paired tumor/peritumor tissues. This research included the collection of 124 tissue samples from 106 patients (106 tumor and 18 lymph node specimens). Samples were methodically arranged into a tissue microarray and treated with immunohistochemical staining. Statistical analysis was conducted to assess the relationship between them. In the univariate analysis, 3 factors were identified as statistically significant in relation to lymph node metastasis: T category (P = .014), vascular invasion (P < .001), and SOX4 intensity (P = .001). Additionally, when evaluating SOX4 intensity alongside other clinical indicators, SOX4 was shown to independently influence lymph node metastasis. Further, the multivariate analysis revealed that vascular invasion (P < .001) and SOX4 intensity (P = .003) were significantly associated with lymph node metastasis, exhibiting hazard ratios of 10.174 and 7.142, respectively. The results of our study indicate that both SOX4 expression and vascular invasion serve as predictors of lymph node metastasis in patients diagnosed with category T1 esophageal squamous cell carcinoma, underscoring the potential utility of SOX4 in prognostic evaluations.

Patients with gastroesophageal reflux disease (GERD) are more likely to develop esophageal cancer (EC). However, a causal relationship between the 2 has been difficult to determine. Therefore, this study aimed to evaluate the impact of GERD on EC using the Mendelian randomization (MR) method. The causal association between GERD and EC was analyzed based on 2 publicly available genetic summary datasets for the GERD cohort (129,080 cases vs 473,524 controls) and the EC cohort (740 cases vs 372,016 controls). The causal inference was mainly evaluated by the inverse variance weighted MR. The MR-Egger regression, MR Pleiotropy Residual Sum and Outlier test, and leave-one-out test were used to confirm the sensitivity of the MR results. Possible interfering factors were excluded by multivariate MR (MVMR) analysis. We used 73 single nucleotide polymorphisms as instrumental variables. GERD was associated with increasing EC risk (odds ratio [OR], 1.001; 95% confidence interval, 1.001-1.002; P < .001), which was identified using the inverse variance weighted method. The sensitivity analysis also demonstrated similar results with the causal explanation, and major bias in genetic pleiotropy was not identified (intercept, 0.001; standard error, 0.001; P = .418). The multivariate MR analysis demonstrated the effect of GERD on EC even after excluding possible mediating factors (OR, 1.003; 95% confidence interval, 1.001-1.005; P = .012). This study confirmed that GERD has a causal effect on EC. Therefore, interventional measures are recommended to prevent EC.

Esophageal squamous cell carcinoma (ESCC) remains an important health concern in developing countries. Patients with advanced ESCC have a poor prognosis and survival rate, and achieving early diagnosis remains a challenge. Metabolic biomarkers are gradually gaining attention as early diagnostic biomarkers. Hence, this multicenter study comprehensively evaluated metabolism dysregulation in ESCC through an integrated research strategy to identify key metabolite biomarkers of ESCC. First, the metabolic profiles were examined in tissue and serum samples from the discovery cohort (n = 162; ESCC patients, n = 81; healthy volunteers, n = 81), and ESCC tissue-induced metabolite alterations were observed in the serum. Afterward, RNA sequencing of tissue samples (n = 46) was performed, followed by an integrated analysis of metabolomics and transcriptomics. The potential biomarkers for ESCC were further identified by censoring gene-metabolite regulatory networks. The diagnostic value of the identified biomarkers was validated in a validation cohort (n = 220), and the biological function was verified. A total of 457 dysregulated metabolites were identified in the serum, of which 36 were induced by tumor tissues. The integrated analyses revealed significant alterations in the purine salvage pathway, wherein the abundance of hypoxanthine/xanthine exhibited a positive correlation with HPRT1 expression and tumor size. A diagnostic model was developed using two purine salvage-associated metabolites. This model could accurately discriminate patients with ESCC from normal individuals, with an area under the curve (AUC) (95% confidence interval (CI): 0.680-0.843) of 0.765 in the external cohort. Hypoxanthine and HPRT1 exerted a synergistic effect in terms of promoting ESCC progression. These findings are anticipated to provide valuable support in developing novel diagnostic approaches for early ESCC and enhance our comprehension of the metabolic mechanisms underlying this disease.

Clinicopathological and molecular studies have demonstrated that dysplasia is a precancerous and/or neoplastic lesion with malignant potential. Further, it is subclassified into two grades: high-grade and low-grade dysplasia. High-grade dysplasia is a clinically significant lesion requiring resection or ablation. Low-grade dysplasia has a much lower risk of carcinoma; thus, it should be followed by endoscopic surveillance. Because squamous dysplasia may progress to squamous cell carcinoma, periodic endoscopy is useful to detect the lesion in patients with risk factors. Squamous dysplasia is diagnosed histopathologically by evaluating both cytologic and structural changes.

Immune checkpoint inhibitors (ICIs) have significantly improved patient survival in multiple cancers. However, therapy response in esophageal cancer is limited to subgroups of patients and clinically useful predictive biomarkers are lacking.

We collected a series of plasma samples from 91 patients with esophageal cancer before and after ICI treatment. The Olink Immuno-Oncology panel (92 proteins) with proximity extension assays was used to detect the dynamic changes in plasma and potential biomarkers associated with treatment outcomes. We screened all survival-related proteins and established a risk score model to better predict the prognosis and treatment response in patients with esophageal cancer immunotherapy.

We found that 47 out of 92 quantified proteins had significant changes in plasma levels during ICI treatment (p<0.050), and these changed proteins were involved in immune-related reactions, such as intercellular adhesion and T-cell activation. Notably, the baseline levels of three angiogenesis-related proteins (IL-8, TIE2, and HGF) were significantly associated with the survival outcomes of patients treated with ICIs (p<0.050). According to these prognostic proteins, we established an angiogenesis-related risk score, which could be a superior biomarker for ICI response prediction. In addition, antiangiogenic therapy combined with ICIs significantly improved overall survival compared with ICI monotherapy (p=0.044).

An angiogenesis-related risk score based on three proteins (IL-8, TIE2, and HGF) could predict ICI response and prognosis in patients with esophageal cancer, which warrants verification in the future. Our study highlights the potential application of combining ICIs and antiangiogenic therapy and supports Olink plasma protein sequencing as a liquid biopsy method for biomarker exploration.

Esophageal squamous cell carcinoma (ESCC) is a common malignant tumor with a poor prognosis due to a lack of early detection. Indeed, the mechanisms underlying ESCC progression remain unclear. Here, we discovered that abnormal arginine metabolism contributes to ESCC progression. Based on transcriptomic and metabolomic analyses, we found that argininosuccinate synthetase 1 (ASS1) and argininosuccinate lyase (ASL) levels were increased in primary tumor tissues but decreased in lymph-metastatic tumor tissues. Intriguingly, FOXO3a was inversely correlated with ASS1 and ASL in primary and metastatic tumor tissues, suggesting that FOXO3a dissimilarly regulates ASS1 and ASL at different stages of ESCC. Silencing ASS1/ASL inhibited primary tumor growth and promoted metastasis. Conversely, overexpression of ASS1/ASL or increased arginine supply promoted tumor proliferation but suppressed metastasis. In addition, FOXO3a activation inhibited primary tumor growth by repressing ASS1 and ASL transcription, whereas inactivation of FOXO3a impeded metastasis by releasing ASS1 and ASL transcription. Together, the finding sheds light on metastatic reprogramming in ESCC.

Limited data are available on the epidemiology of gastroesophageal junction adenocarcinoma (GEJAC), particularly in comparison to esophageal adenocarcinoma (EAC). With the advent of molecular non-endoscopic Barrett's esophagus (BE) detection tests which sample the esophagus and gastroesophageal junction, early detection of EAC and GEJAC has become a possibility and their epidemiology has gained importance.

We sought to evaluate time trends in the epidemiology and survival of patients with EAC and GEJAC in a population-based cohort.

EAC and GEJAC patients from 1976 to 2019 were identified using ICD 9 and 10 diagnostic codes from the Rochester Epidemiology Project (REP). Clinical data and survival status were abstracted. Poisson regression was used to calculate incidence rate ratios (IRR). Survival analysis and Cox proportional models were used to assess predictors of survival.

We included 443 patients (287 EAC,156 GEJAC). The incidence of EAC and GEJAC during 1976-2019 was 1.40 (CI 1.1-1.74) and 0.83 (CI 0.61-1.11) per 100,000 people, respectively. There was an increase in the incidence of EAC (IRR = 2.45, p = 0.011) and GEJAC (IRR = 3.17, p = 0.08) from 2000 to 2004 compared to 1995-1999, plateauing in later time periods. Most patients had associated BE and presented at advanced stages, leading to high 5-year mortality rates (66% in EAC and 59% in GEJAC). Age and stage at diagnosis were predictors of mortality.

The rising incidence of EAC/GEJAC appears to have plateaued somewhat in the last decade. However, both cancers present at advanced stages with persistently poor survival, underscoring the need for early detection.

Despite the usefulness of white light endoscopy (WLE) and non-magnified narrow-band imaging (NBI) for screening for superficial oesophageal squamous cell carcinoma and precancerous lesions, these lesions might be missed due to their subtle features and interpretation variations among endoscopists. Our team has developed an artificial intelligence (AI) system to detect superficial oesophageal squamous cell carcinoma and precancerous lesions using WLE and non-magnified NBI. We aimed to evaluate the auxiliary diagnostic performance of the AI system in a real clinical setting.

We did a multicentre, tandem, double-blind, randomised controlled trial at 12 hospitals in China. Eligible patients were aged 18 years or older and underwent sedated upper gastrointestinal endoscopy for screening, investigation of gastrointestinal symptoms, or surveillance. Patients were randomly assigned (1:1) to either the AI-first group or the routine-first group using a computerised random number generator. Patients, pathologists, and statistical analysts were masked to group assignment, whereas endoscopists and research assistants were not. The same endoscopist at each centre did tandem upper gastrointestinal endoscopy for each eligible patient on the same day. In the AI-first group, the endoscopist did the first examination with the assistance of the AI system and the second examination without it. In the routine-first group, the order of examinations was reversed. The primary outcome was the miss rate of superficial oesophageal squamous cell carcinoma and precancerous lesions, calculated on a per-lesion and per-patient basis. All analyses were done on a per-protocol basis. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR2100052116) and is completed.

Between Oct 19, 2021, and June 8, 2022, 5934 patients were randomly assigned to the AI-first group and 5912 to the routine-first group, of whom 5865 and 5850 were eligible for analysis. Per-lesion miss rates were 1·7% (2/118; 95% CI 0·0-4·0) in the AI-first group versus 6·7% (6/90; 1·5-11·8) in the routine-first group (risk ratio 0·25, 95% CI 0·06-1·08; p=0·079). Per-patient miss rates were 1·9% (2/106; 0·0-4·5) in AI-first group versus 5·1% (4/79; 0·2-9·9) in the routine-first group (0·37, 0·08-1·71; p=0·40). Bleeding after biopsy of oesophageal lesions was observed in 13 (0·2%) patients in the AI-first group and 11 (0·2%) patients in the routine-first group. No serious adverse events were reported by patients in either group.

The observed effect of AI-assisted endoscopy on the per-lesion and per-patient miss rates of superficial oesophageal squamous cell carcinoma and precancerous lesions under WLE and non-magnified NBI was consistent with substantial benefit through to a neutral or small negative effect. The effectiveness and cost-benefit of this AI system in real-world clinical settings remain to be further assessed.

National Natural Science Foundation of China, 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University, and Chengdu Science and Technology Project.

For the Chinese translation of the abstract see Supplementary Materials section.

Esophageal cancer is a highly incidence and deadly disease with a poor prognosis, especially in developing countries. Owing to the lack of specific symptoms and early diagnostic biomarkers, most patients are diagnosed with advanced disease, leading to a 5-year survival rate of less than 15%. Early (n = 50) and middle-advanced (n = 50) esophageal squamous cell carcinoma (ESCC) patients, as well as 71 healthy individuals, underwent 5-hydroxymethylcytosine (5hmC) sequencing on their plasma cell-free DNA (cfDNA). A Northern Chinese cohort of cfDNA 5hmC dataset of 150 ESCC patients and 183 healthy individuals were downloaded for validation. A diagnostic model was developed using cfDNA 5hmC signatures and then improved by low-pass whole genome sequencing (WGS) features of cfDNA. Conserved cfDNA 5hmC modification motifs were observed in the two independent ESCC cohorts. The diagnostic model with 5hmC features achieved an AUC of 0.810 and 0.862 in the Southern and Northern cohorts, respectively, with sensitivities of 69.3-74.3% and specificities of 82.4-90.7%. The performance was well maintained in Stage I to Stage IV, with accuracy of 70-100%, but low in Stage 0, 33.3%. Low-pass WGS of cfDNA improved the AUC to 0.934 with a sensitivity of 82.4%, a specificity of 88.2%, and an accuracy of 84.3%, particularly significantly in Stage 0, with an accuracy up to 80%. 5hmC and WGS could efficiently differentiate very early ESCC from healthy individuals. These findings imply a non-invasive and convenient method for ESCC detection when clinical treatments are available and may eventually prolong survival.

Esophageal squamous cell carcinoma (ESCC) develops through a series of increasingly abnormal precancerous lesions. Previous studies have revealed the striking differences between normal esophageal epithelium and ESCC in copy number alterations (CNAs) and mutations in genes driving clonal expansion. However, due to limited data on early precancerous lesions, the timing of these transitions and which among them are prerequisites for malignant transformation remained unclear. Here, we analyze 1,275 micro-biopsies from normal esophagus, early and late precancerous lesions, and esophageal cancers to decipher the genomic alterations at each stage. We show that the frequency of TP53 biallelic inactivation increases dramatically in early precancerous lesion stage while CNAs and APOBEC mutagenesis substantially increase at late stages. TP53 biallelic loss is the prerequisite for the development of CNAs of genes in cell cycle, DNA repair, and apoptosis pathways, suggesting it might be one of the earliest steps initiating malignant transformation.