Microbiota and esophageal cancer: From dysbiosis to carcinogenesis.

Background: Esophageal cancer (EC) is one of the deadliest cancers in the world. However, the mechanism that drives the evolution of EC is still unclear. On this basis, we identified the key genes and molecular pathways that may be related to the progression of esophageal adenocarcinoma and squamous cell carcinoma to find potential markers or therapeutic targets.Methods: GSE26886 were obtained from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) among normal samples, EA, and squamous cell carcinoma were determined using R software. Then, potential functions of DEGs were determined using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The STRING software was used to identify the most important modules in the protein–protein interaction (PPI) network. The expression levels of hub genes were confirmed using UALCAN database. Kaplan–Meier plotters were used to confirm the correlation between hub genes and outcomes in EC.Results: In this study, we identified 1,098 genes induced in esophageal adenocarcinoma (EA) and esophageal squamous cell carcinoma (ESCC), and 669 genes were reduced in EA and ESCC, suggesting that these genes may play an important role in the occurrence and development of EC tumors. Bioinformatics analysis showed that these genes were involved in cell cycle regulation and p53 and phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. In addition, we identified 147 induced genes and 130 reduced genes differentially expressed in EA and ESCC. The expression of ESCC in the EA group was different from that in the control group. By PPI network analysis, we identified 10 hub genes, including GNAQ, RGS5, MAPK1, ATP1B1, HADHA, HSDL2, SLC25A20, ACOX1, SCP2, and NLN. TCGA validation showed that these genes were present in the dysfunctional samples between EC and normal samples and between EA and ESCC. Kaplan–Meier analysis showed that MAPK1, ACOX1, SCP2, and NLN were associated with overall survival in patients with ESCC and EA.Conclusions: In this study, we identified a series of DEGs between EC and normal samples and between EA and ESCC samples. We also identified 10 key genes involved in the EC process. We believe that this study may provide a new biomarker for the prognosis of EA and ESCC.

Esophageal squamous cell carcinomas (ESCCs) and esophageal adenocarcinomas (EACs) account for >95% of esophageal malignancies and represent a major global health burden. ESCC is the dominant histology globally but represents a minority of U.S. cases, with EAC accounting for the majority of U.S. The patient outcomes for advanced ESCC and EAC are poor, and new therapeutic options are needed. Using a sensitive sequencing assay, we compared the genomic profiles of ESCC and EAC with attention to identification of therapeutically relevant genomic alterations. Next-generation sequencing-based comprehensive genomic profiling was performed on hybridization-captured, adaptor ligation-based libraries to a median coverage depth of >650× for all coding exons of 315 cancer-related genes plus selected introns from 28 genes frequently rearranged in cancer. Results from a single sample were evaluated for all classes of genomic alterations (GAs) including point mutations, short insertions and deletions, gene amplifications, homozygous deletions, and fusions/rearrangements. Clinically relevant genomic alterations (CRGAs) were defined as alterations linked to approved drugs and those under evaluation in mechanism-driven clinical trials. There were no significant differences by sex for either tumor type, and the median age for all patients was 63 years. All ESCCs and EACs were at an advanced stage at the time of sequencing. All 71 ESCCs and 231 EACs featured GAs on profiling, with 522 GAs in ESCC (7.4 per sample) and 1,303 GAs in EAC (5.6 per sample). The frequency of clinically relevant GAs in ESCC was 94% (2.6 per sample) and 93% in EAC (2.7 per sample). CRGAs occurring more frequently in EAC included KRAS (23% EAC vs. 6% ESCC) and ERBB2 (23% EAC vs. 3% ESCC). ESCC samples were enriched for CRGA in PIK3CA (24% ESCC vs. 10% EAC), PTEN (11% ESCC vs. 4% EAC), and NOTCH1 (17% ESCC vs. 3% EAC). Other GAs that differed significantly between histologic tumor types included SMAD4 (14% EAC vs. 1% ESCC), RB1 (14% ESCC vs. 2% EAC), SOX2 (18% ESCC vs. 1% EAC), and NFE2L2 (24% ESCC vs. 1% EAC). ESCC and EAC share similarly high frequencies of overall and clinically relevant genomic alterations; however, the profiles of genomic alterations in the two diseases differ widely, with KRAS and ERBB2 far more frequently altered in EAC compared with ESCC and with mammalian target of rapamycin (MTOR) pathway genes (PIK3CA and PTEN) and NOTCH1 more frequently altered in ESCC compared with EAC. Comprehensive genomic profiling highlights the promise of identifying clinically relevant genomic alterations in both ESCC and EAC and suggests new avenues for molecularly directed therapies in esophageal cancer.

184 Background: Global neoadjuvant and adjuvant treatment patterns among patients with resected Esophageal Cancer (EC) and Gastroesophageal Junction cancer (GEJC) remain unclear. This study describes real-world treatment patterns and outcomes for patients receiving surgery for Stage II or III EC or GEJC. Methods: Physicians in North America (US, Canada), Asia (China, Japan, Taiwan), and Europe (UK, France, Germany, Italy, Spain) provided clinical and treatment data in this retrospective, non-interventional chart review conducted from April-June 2020. Included patients were adults (Japan ≥20 years; elsewhere, ≥18 years), who underwent resection of Stage II or III EC or GEJC between October 2017 and October 2018 and were followed until death, loss to follow up, or end of data collection. Results: Physicians (N = 609) provided data on 1693 patients of mean age of 62.4 years, who received surgery for Stage II or III esophageal squamous cell carcinoma (ESCC) (33.3%), esophageal adenocarcinoma (EAC) (31.5%), or GEJC (35.2%) and were followed a mean (median) of 17.7 (17) months (to death or end of study period). At diagnosis, 85.6% of patients had performance status of 0/1. The majority of patients received an R0 resection (overall, 70.6%; ESCC, 76.6%, EAC, 67.4%, GEJC, 68.0%; p < 0.05); of these, 32.0% had a complete pathological response and 64.1% had a partial pathological response. Neoadjuvant therapy use differed among the treatment groups (ESCC 56.5%; EAC, 65.9%; GEJC, 62.6%, p < 0.05), as did adjuvant therapy (ESCC: 39.8%; EAC, 40.3%; GEJC, 44.5%; p = 0.023). Recurrence rate following surgery did not differ between groups for any recurrence (overall, 21.0%; ESCC 18.5%, EAC 23.6%, GEJC 21.1%); for local or regional recurrence (overall, 11.6%; ESCC, 10.3%; EAC, 12.7%; GEJC, 11.7%); or for metastatic recurrence (overall, 9.5%; ESCC, 8.2%; EAC, 10.9%; GEJC, 9.4%). The median time to local or regional recurrence (for those who progressed during the reporting period) was 8 months from date of initial surgery (overall, 8 mo; ESCC, 8 mo; EAC, 7 mo; GEJC, 8.5 mo; p > 0.05). The frequency of 1L systemic therapy for advanced disease at the time of survey completion was 16.1% overall and differed among patients with ESCC (14.6%); EAC (17.8%); and GEJC (15.9%); p > 0.05. Conclusions: This large multi-country real world data study shows that over half of all patients received neoadjuvant therapy, and over a third received adjuvant treatment. The high unmet need in this population is evident from the post-resection recurrence rate of 21.1% at median 8 months and the high proportion of patients who went on to require advanced disease treatment.

Esophageal cancer is the eighth most common cancer worldwide and the majority of patients have systemic disease at presentation. Esophageal adenocarcinoma (OAC), the predominant subtype in western countries, is largely resistant to current chemotherapy regimens. Selective markers are needed to enhance clinical staging and to allow targeted therapies yet there are minimal proteomic data on this cancer type. After histological review, lysates from OAC and matched normal esophageal and gastric samples from seven patients were subjected to LC MS/MS after tandem mass tag labeling and OFFGEL fractionation. Patient matched samples of OAC, normal esophagus, normal stomach, lymph node metastases and uninvolved lymph nodes were used from an additional 115 patients for verification of expression by immunohistochemistry (IHC).Over six thousand proteins were identified and quantified across samples. Quantitative reproducibility was excellent between technical replicates and a moderate correlation was seen across samples with the same histology. The quantitative accuracy was verified across the dynamic range for seven proteins by immunohistochemistry (IHC) on the originating tissues. Multiple novel tumor-specific candidates are proposed and EPCAM was verified by IHC.This shotgun proteomic study of OAC used a comparative quantitative approach to reveal proteins highly expressed in specific tissue types. Novel tumor-specific proteins are proposed and EPCAM was demonstrated to be specifically overexpressed in primary tumors and lymph node metastases compared with surrounding normal tissues. This candidate and others proposed in this study could be developed as tumor-specific targets for novel clinical staging and therapeutic approaches.

Esophageal cancer can present as two histological subtypes of esophageal cancer, adenocarcinoma or squamous cell carcinoma. The vast majority, if not all, esophageal adenocarcinomas arise from Barrett’s esophagus. Similarly, squamous dysplasia carries an elevated risk of progression to esophageal squamous cell carcinoma. Both cancer types have extremely poor survival rates, and therefore there is an acute need to identify modifiable risk factors that may help to prevent their development. Despite the mechanistic and ecological support for a general anti-carcinogenic role of vitamin D, studies in relation to esophageal cancer have illustrated conflicting results. Studies of vitamin D intake have been inversely associated with squamous cell carcinoma risk and directly associated with adenocarcinoma risk in European studies, while no significant associations were observed in an American case–control study. Contradictory to this, evidence from high quality prospective cohorts have illustrated that low levels of circulating vitamin D are associated with a reduced risk of esophageal squamous cell carcinoma, particularly in Asian populations. Small studies of vitamin D related genetic variants have failed to detect an association with the risk of either histological subtype of esophageal cancer. Laboratory investigations do suggest, however, that vitamin D receptor expression is more apparent in Barrett’s esophagus and esophageal adenocarcinoma tissue, and therefore are more likely to interact with vitamin D intake or status to impact on outcomes compared with squamous cell carcinomas. Whether these are positive or negative influences on development or survival remains unclear. Further work is clearly warranted in this area to fully understand the mechanisms involved and to clarify the conflicting evidence to date.

It is important to note that although the current treatment for advanced esophageal cancer (EC) has made great technological advances, patients' 5-year survival rates do not appear to be encouraging. Therefore, understanding the clinicopathological features and metastasis patterns of the patients with stage IV EC, combined with the prognosis of these patients, can aid in choosing the optimal treatment plan. It is well known that esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are the two most common pathological types. The aim of this study is to examine and compare the clinicopathological features and metastatic modes of stage IV ESCC and EAC, as well as their prognosis and survival. Based on the Surveillance, Epidemiology, and End Results (SEER) database, we assessed the characteristics of ESCCs and EACs associated with prognosis using the Kaplan-Meier survival analysis, and the Cox regression model. Furthermore, the clinical data of 217 patients with stage IV ESCC and EAC in the Department of Gastroenterology of the Second Affiliated Hospital of Nantong University between 2014 and 2016 were reviewed. A total of 3,707 cases treated between 2010 and 2016 were included. The incidence of EAC in the United States is much higher than that of ESCC. Common metastasis patterns were lungs only, liver only, bones only, and lung & liver. The multivariate Cox analysis showed that treatment mode and metastasis patterns were independent risk factors affecting the overall survival (OS) time of patients (stage IV ESCC & EAC). EAC patients with only lung metastases may have a longer survival if chose treatment options that included surgery. In the external cohort, a total of 217 cases were included. The prevalence of ESCC is much higher than that of EAC, and the common metastasis patterns are liver only, lung only, and liver & lung. The multivariate Cox analysis showed that treatment mode was independent risk factor affecting the OS time of patients (stage IV ESCC & EAC). EAC patients treated with surgery combined with chemoradiotherapy may have a better prognosis. In general, the prognosis of patients with stage IV ESCC and EAC are poor. However, surgery was found to significantly improve the OS time of patients with stage IV EAC in this study.

7 Background: ESCC and EAC are relatively rare malignancies in the US with EAC more common than ESCC. Using a sensitive CGP assay, we compared the genomic profiles of ESCC and EAC focused on the search for therapy targets. Methods: DNA was extracted from 40u of FFPE sections from 54 clinically advanced ESCC and 234 EAC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a median coverage depth of 652X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The results were evaluated for all classes of genomic alterations (GA) including point mutations, short INDELs, copy number alterations and fusions/rearrangements. Clinically relevant genomic alterations (CRGA) were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: All ESCC and EAC were at an advanced stage (Stage III/IV) at the time of CGP and had similar gender and age (median 63 yrs) distribution. 54 (100%) of ESCC and 233 (99.6%) of EAC featured GA on profiling with 397 GA in ESCC (7.4/sample) and 1,317 GA (5.6/sample) in EAC. The frequency of clinically relevant GA in ESCC (2.7/sample; 93% of cases) and EAC (2.7/sample; 92% of cases) were identical. EAC featured a greater number of CRGA (72) than ESCC (46). CRGA more frequently altered in EAC than ESCC included KRAS (23% vs 7%) and ERBB2 (23% vs 4%). CRGA more frequently identified in ESCC than EAC included PIK3CA (28% vs 10%), PTEN (13% vs 4%) and NOTCH1 (22% vs 3%). Other GA that were significantly different in the 2 tumor types included SMAD4 (14% EAC vs 0% ESCC), RB1 (19% ESCC vs 2% EAC), SOX2 (17% ESCC vs 1% EAC) and NFE2L2(19% ESCC vs 0% EAC). HPV-16 was detected in 2 (4%) and HPV-18 in 1 (2%) of ESCC. HPV was not detected in EAC. Conclusions: ESCC and EAC share high frequencies of total GA and CRGA. However, KRAS and ERBB2 are far more frequently altered in EAC than ESCC and mTOR pathway genes (PIK3CA and PTEN) more frequently altered in ESCC than EAC. CGP shows significant promise to identify CRGA in both ESCC and EAC and drive the potential use of clinical outcome altering targeted therapies in both major types of esophageal cancer.

Comparative Genomics of Esophageal Adenocarcinoma and Squamous Cell Carcinoma

Erratum: salt tea consumption and esophageal cancer: a possible role of alkaline beverages in esophageal carcinogenesis.

IntroductionThe role of CD147 as an important indicator of tumor prognosis remains controversially discussed in literature. We focused on the prognostic significance of CD147 expression in esophageal cancer patients. While some studies report that CD147 is an unfavorable prognostic factor in esophageal squamous cell carcinoma, others showed no significant correlation. However, only one study draws attention to the significance of CD147 in esophageal adenocarcinoma, which is one of the most rapidly increasing neoplasms in the western world.MethodsTo finally clarify the impact of CD147 as a prognostic factor, especially for esophageal adenocarcinomas, we analyzed CD147 expression in a tissue microarray of 359 esophageal adenocarcinomas and 254 esophageal squamous cell cancer specimens. For the immuno-histochemical analysis, we used a primary antibody specific for CD147. Staining intensity and proportion of positive tumor cells were scored (negative, weak, moderate, strong staining). These findings were compared to normal esophageal tissue and correlated to the histopathological tumor phenotype and survival data.ResultsCD147 expression was detectable in weak intensities in benign esophageal tissue (85.78%) and expressed in predominately moderate to strong intensities in esophageal cancer (88.34%). Strong CD147 immunostaining was linked to increased infiltration depth (p = 0.015) and differentiation (p = 0.016) in esophageal squamous cell cancer but revealed no significant correlation with histopathology of adenocarcinoma. Moreover, CD147 intensity was unrelated to overall survival in this collective for both subtypes of esophageal cancer.ConclusionThus, our data show that CD147 has no prognostic value, neither in esophageal adenocarcinoma nor squamous cell carcinoma.

Esophageal cancer (EC) consists of two main histological subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), each with distinct epidemiological patterns. Historically, ESCC has been the dominant subtype worldwide, especially in Asian countries. However, in recent decades, the incidence of EAC has been rising rapidly, particularly in European and American countries, reflecting significant shifts in global EC epidemiology. This study presents a comprehensive analysis of 25 years of high-quality continuous data on ESCC and EAC incidence trends across 25 countries. It highlights declining ESCC rates in most regions, rising EAC rates in Western nations, pronounced sex differences, and narrowing ESCC-to-EAC ratios. These diverse trends reveal the need to investigate region-specific risk factors and their contributions to the shifting burden of EC globally. The distinct trends of ESCC and EAC call for tailored public health strategies based on regional and histological patterns. Countries experiencing a rising burden of EAC or ESCC can implement targeted risk factor prevention and control measures to address the increasing trends. In clinical practice, a stronger focus on EAC in high-income countries and ESCC in regions, where it remains dominant, can improve early detection and treatment outcomes. Understanding these evolving patterns will aid in designing evidence-based interventions and optimizing resource allocation to reduce the global esophageal cancer burden effectively.

Helicobacter pylori (H.pylori) is associated with lower risks of Barrett's esophagus and esophageal adenocarcinoma, but whether H.pylori eradication increases the risk of these conditions is unknown. This study aimed to test the hypothesis that H.pylori eradication leads to gradually increased risks of Barrett's esophagus and esophageal adenocarcinoma over time, while esophageal squamous cell carcinoma was assessed for comparison reasons. This Swedish nationwide, population-based cohort study in 2005-2012 used data from the Swedish Prescribed Drug Registry to assess eradication treatment for H.pylori. Barrett's esophagus was identified from the Swedish Patient Registry, and esophageal adenocarcinoma and squamous cell carcinoma from the Swedish Cancer Registry. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated by dividing the observed risk in the H.pylori eradication treatment cohort by the expected risk derived from the Swedish population of the same age, sex, and calendar period. The cohort included 81919 patients having had eradication treatment. For Barrett's esophagus (n=178), the overall SIR was increased (SIR 3.67, 95% CI 3.15-4.25), but the SIRs slightly decreased over time after eradication treatment. For esophageal adenocarcinoma (n=11), the overall SIR was 1.26 (95% CI 0.62-2.26), and the SIRs did not increase over time. The SIRs of esophageal squamous cell carcinoma (n=10) were not influenced by eradication treatment. This study did not provide any evidence of an increasing risk of Barrett's esophagus or esophageal adenocarcinoma (or esophageal squamous cell carcinoma) over time after eradication treatment for H.pylori.

Nutrition deficiencies or poverty traditionally have been recognized to be related with increased risk for esophageal cancer (EC) in rural regions at junction of Henan, Hebei, and Shanxi provinces in northern China--the highest incidence area for esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA). Since the 1980s, economic and nutrition condition in these areas have been improved greatly. However, the histopathological types, staging pattern, and occurrence of ESCC and GCA, especially for esophageal adenocarcinoma (EAC), which have been rarely examined in the Chinese population during the past decades in these areas have not been well characterized to date. Yearly diagnosed new esophageal cancer (ESCC and EAC) and GCA patients from Beijing Tongren Hospital (in municipal low-risk region) and Cixian People Hospital (in rural high-risk region) during 24-year period (1982-2005) were studied retrospectively. Only local resident patients with surgical resection were included. Age at diagnosis, tumor stage and site, and histopathological pattern were recorded for each patient from the tumor registry database in these hospitals. This study demonstrated that the common ESCC sites were different in municipal (chiefly in lower third of the esophagus) and in rural (chiefly in middle third of the esophagus) regions. The peak age of ESCC, EAC, and GCA patients in rural region was 10 years younger than in municipal region. Eighty-six percent of ESCC and 90% of GCA in municipal region were diagnosed at middle and advanced stage; similarly, more than 95% of ESCC and GCA in rural region were diagnosed at middle and advanced stage during the 24-year study period. An increasing tendency in number of yearly diagnosed new patients with ESCC and GCA was observed in municipal region, but not in rural region. However, an increasing tendency for EAC was observed both in municipal and rural regions during the past 24-year period. The present results demonstrate the difference in municipal and rural regions of ESCC, ECA, and GCA in histopathological types, and suggest that there may be different etiological factors involved in esophageal and gastric cardia carcinogenesis in these different areas.

AGA Clinical Practice Update on the Utility of Endoscopic Submucosal Dissection in T1b Esophageal Cancer: Expert Review

Background Diet may affect esophageal and gastric cancer risk, but associations have been inconsistent. Due to the complexity of the diet, studies of dietary patterns may elucidate the associations between diet and cancer better than studies of individual foods. Yet, studies evaluating the association between index-based dietary patterns and incident esophageal and gastric cancers have been sparse. Objectives We aimed to prospectively evaluate the association between two diet quality indices, the Healthy Eating Index-2005 (HEI-2005) and the alternate Mediterranean Diet Score (aMED), and risk of esophageal and gastric cancers in the United States. Methods In sum, 494,968 participants from the National Institutes of Health-AARP Diet and Health study completed a self-administered baseline food frequency questionnaire which was used to estimate scores for each index. Results During the follow-up (1995-2006), we documented 215 esophageal squamous cell carcinomas (ESCC), 633 esophageal adenocarcinomas (EAC), 453 gastric cardia adenocarcinomas, and 501 gastric noncardia adenocarcinomas. Higher scores in the HEI-2005, reflecting healthy eating patterns, were associated with a reduced risk of ESCC (the highest quintile compared to lowest: hazard ratio (HR) =0.51, 95% confidence interval (CI): 0.31-0.86, Ptrend =0.001), and EAC (HR=0.75, 95% CI: 0.57-0.98, Ptrend=0.01). We observed an inverse association of ESCC with higher diet quality as assessed by aMED, but not for EAC. No significant associations for gastric cardia or noncardia adenocarcinomas were found with either HEI-2005 or aMED. Conclusions In this prospective study, the HEI-2005 was inversely associated with risk of both ESCC and EAC, while the aMED was associated with reduced risk of ESCC, suggesting that adherence to dietary recommendations may help prevent esophageal cancer. Citation Format: Wen-qing Li, Yikyung Park, Jennifer W. Wu, Jian-song Ren, Alisa M. Goldstein, Philip R. Taylor, Albert R. Hollenbeck, Neal D. Freedman, Christian C. Abnet. Index-based dietary patterns and risk of esophageal cancer and gastric cancer in the NIH-AARP diet and health study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4805. doi:10.1158/1538-7445.AM2013-4805