Incidence Of Esophageal Adenocarcinoma Research Articles

Esophageal cancer (EC) is a leading cause of cancer-related death in the west 1 . Esophageal squamous cell carcinoma (SCC) is the most common type of EC worldwide. However, in Western countries, including the United States, esophageal adenocarcinoma (EAC) is the most common 2 . EAC is most common in the lower esophagus whereas SCC is most common in the middle and upper esophagus 3 . The incidence of EAC has increased dramatically in western countries over the past few decades. 2 3 The exact reason for this rise in EAC has not been clearly understood. However, an increase in the prevalence of EAC risk factors is postulated as a potential explanation 4 . Although there are many identifiable EAC risk factors, including gastroesophageal reflux disease (GERD), obesity, male sex, White race, and smoking 5 6 7 , Barrett's esophagus (BE) remains the major precursor lesion of esophageal adenocarcinoma. BE develops when there is a change in the normal squamous lining of the esophageal mucosa into intestinal metaplasia 8 9 . The incidence has also increased in the population over the past few decades 10 11 . There is a well-described progression within BE from non-dysplastic BE (NDBE), low-grade dysplasia (LGD), high-grade dysplasia (HGD), intramucosal carcinoma (IMC), to invasive EAC 12 13 . Recent data suggest that the increased incidence of EAC may have plateaued 1 . However, we questioned whether the prevalence of EAC is still increasing, especially at younger ages in lieu of recent trends showing an increase in the prevalence of colorectal cancer in younger patients. These findings resulted in a lowering of the colorectal cancer screening age cutoff to 45 years from 50 years 14 15 16 . Therefore, we aimed to assess the time trends in the prevalence and incidence of EAC and some of its risk factors in a large population of patients in Florida and to assess these trends based on age categories. We hypothesized that the prevalence of EAC and BE has increased over time at younger age groups.

BACKGROUNDEsophageal carcinoma presents as 2 types, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) with the frequency of both changing in the United States (US).AIMTo investigate EAC/ESCC incidence time trends among the 3 main US racial groups and investigate trends in US EAC survival by ethnicity.METHODSTwenty-five years (1992-2016) of data from SEER 13 program was analyzed to compare incidence trends in EAC and ESCC between non-Hispanic whites (nHW), non-Hispanic Blacks (nHB) and Hispanics (Hisp) using SEERStat®. In addition, SEER 18 data, from 1975-2015, on EAC in the US was analyzed to evaluate racial disparities in incidence and survival using SEERStat® and Ederer II method.RESULTSIn the 3 major US ethnic groups, age-adjusted incidence of ESCC has declined while EAC has continued to rise from 1992-2016. Of note, in Hisp, the EAC incidence rate increased while ESCC decreased from 1992 to 2016, resulting in EAC as the predominant esophageal cancer subtype in this group since 2011, joining nHW. Furthermore, although ESCC remains the predominant tumor in nHB, the difference between ESCC and EAC has narrowed dramatically over 25 years. EAC survival probabilities were worse in all minority groups compared to nHw.CONCLUSIONHisp have joined nHW as US ethnic groups more likely to have EAC than ESCC. Of note, EAC incidence in nHB is increasing at the highest rate nationally. Despite lower EAC incidence in all minority groups compared to nHW, these populations have decreased survival compared to nHW.

Incidence of Esophageal Adenocarcinoma Among Symptomatic Reflux Patients Without Erosive Disease on Endoscopy is Similar to the General Population

Endoscopic eradication therapy (EET) is the preferred treatment for Barrett's esophagus (BE)-related neoplasia patients. However, the impact of EET on critical outcomes, outside of clinical trials and registry data, remains scarcely studied. We aimed to assess real-world practice patterns and clinical outcomes among BE patients undergoing EET. TriNetX is a large research network comprising linked inpatient and outpatient electronic-health record-derived data from over 80,000,000 patients. Patients with a diagnosis of BE from 2015 to 2020 were identified and included if they underwent EET during the study period. The primary outcome was the progression to EAC after index EET. Secondary outcomes included rate of esophagectomy, and all-cause mortality. All outcomes were stratified by baseline histology. The incidence of EAC and all-cause mortality were reported in person-years and adjusted for age and sex. A total of 4114 patients were analyzed. Distribution of baseline histology was as follows: NDBE (11.8%), LGD (21.4%), HGD (26.4%), EAC (20.8%), and unspecified (19.6%). The total incidence of EAC after index EET was 6.01 per 1000 person-years (PY) for the entire cohort with the highest rate in HGD patients (12.9/1000 PY). The incidence of all-cause mortality was 13.23 per 1000 PY with the highest rates in EAC patients (25.1 per 1000 PY). Rates of esophagectomy were < 1% for all grades of dysplasia. The results of this study provide "real-world" data on critical outcomes for BE patients undergoing EET, demonstrating a low risk of incident EAC, all-cause mortality, and need for esophagectomy.

Esophageal cancer (EC) is a common cancer affecting many regions of the world and carries significant morbidity and mortality. In this article, we review the key risk factors and their associated impact on the changing incidence and prevalence of EC subtypes within different global regions. We also highlight potential reasons for the ever-changing epidemiology of this prevalent cancer type. There has been a shift in incidence of Esophageal Adenocarcinoma (AC) and Squamous Cell Carcinoma (SCC) within certain populations primarily due to an increase prevalence of primary risk factors. In Western nations, more often the United States, there has been a shift from SCC predominance to the majority of new cases of EC being adenocarcinoma. This shift within the United States has largely correlated with a rise in obesity. The prevalence of AC in Asia is also starting to rise as more countries adopt a western diet. The pathophysiology, associated risk factors, and presentation of ESCC and AC are different. This difference is seen in varying lifestyles, population health, and certain genetic risks. With further development closer analysis of primary risk factors and implementation of policies and programs that promote public health literacy, there is a potential to decrease esophageal cancer's global disease burden.

Barrett's esophagus and esophageal cancer after sleeve gastrectomy. Myth or reality?

The incidence of esophageal adenocarcinoma (EAC) has risen rapidly during the past four decades, making it the most common type of esophageal cancer in the USA and Western countries. The NEK (Never in mitosis A (NIMA) related kinase) gene family is a group of serine/threonine kinases with 11 members. Aberrant expression of NEKs has been recently found in a variety of human cancers and plays important roles in tumorigenesis, progression, and drug-resistance. However, the expression of the NEKs in EAC and its precancerous condition (Barrett's esophagus, BE) has not been investigated. In the present study, we first analyzed the TCGA and 9 GEO databases (a total of 10 databases in which 8 contain EAC and 6 contain BE) using bioinformatic approaches for NEKs expression in EAC and BE. We identified that several NEK members, such as NEK2 (7/8), NEK3 (6/8), and NEK6 (6/8), were significantly upregulated in EAC as compared to normal esophagus samples. Alternatively, NEK1 was downregulated in EAC as compared to the normal esophagus. On the contrary, genomic alterations of these NEKs are not frequent in EAC. We validated the above findings using qRT-PCR and the protein expression of NEKs in EAC cell lines using Western blotting and in primary EAC tissues using immunohistochemistry and immunofluorescence. Our data suggest that frequent upregulation of NEK2, NEK3, and NEK7 may be important in EAC.

ObjectiveTo assess the incidence rate of oesophageal adenocarcinoma among patients with non-erosive gastro-oesophageal reflux disease compared with the general population.DesignPopulation based cohort study.SettingAll patients in hospital and specialised outpatient healthcare...

Predicting Incident Adenocarcinoma of the Esophagus or Gastric Cardia Using Machine Learning of Electronic Health Records

The incidence of esophageal adenocarcinoma (EAC) has risen dramatically over the last decade. Over this same period, our understanding and treatments have been revolutionized. Just over a decade ago, the majority of patients with locally advanced esophageal cancer went directly to surgery and our overall survival was bleak. Our current strategy for locally advanced esophageal adenocarcinoma is a multi-disciplinary approach. This approach consists of chemotherapy plus or minus radiation followed by surgical resection followed by adjuvant immunotherapy with the presence of any residual disease. Therefore, now more than ever, the goals of surgery are to minimize morbidity, provide aggressive local control and allow patients to receive to quickly recover so they can receive adjuvant systemic therapy. Surgery continues to play a crucial role in the multi-disciplinary approach to EAC. This review will highlight the on-going areas of controversy in surgical treatment. These controversies are around surgical selection, perioperative decision making and the role of surgery. Specifically, there are controversies in the type of surgical approach offered. This review will discuss the benefits of minimally invasive versus open esophagectomy. The indications for gastrectomy versus esophagectomy in patients with gastroesophageal junction EAC. Further, at the time of operation, there is still debate and on-going trials addressing the addition of a pyloric intervention. Lastly, as we push the limits of systemic therapy, there are those who may not even need a surgical resection. This review will cover the most recent data on selective esophageal resection and the concerns regarding this approach.

This narrative review discusses Barrett's esophagus management in the context of perceived deficiencies or controversies. Barrett's adenocarcinoma incidence has not clearly been impacted by Barrett's screening and surveillance. The following report was derived from articles using PubMed and Google searches. The search was concentrated on Barrett's esophagus screening and management guidelines. Comprehensive literature searches that highlight potential deficiencies or controversies regarding the current approach to Barrett's esophagus were employed. Esophageal adenocarcinoma incidence is rapidly increasing and this malignancy usually presents in an advanced and unresectable state. This is despite the significant expenditure of resources and time in endoscopic screening for and surveillance of Barrett's esophagus. Thus, more widespread screening for Barrett's esophagus may be considered. In addition, there are apparent inefficiencies and precision lack in the performance of endoscopic surveillance. This relates mainly to the lack of endoscopic cues for dysplasia. On the other hand, relatively low-risk subjects have frequent screening or surveillance procedures increasing cost. Lastly, endoscopic ablation for Barrett's with dysplasia has moderately good efficacy, especially for eradication of dysplasia, but mandates intensive post-therapy endoscopic surveillance. There is some concern for subsurface development of advanced Barrett's lesions. Fortunately, there is intense research in improving Barrett's esophagus diagnosis and treatment. Our narrative review will delineate deficiencies and potential measures to remedy them. In conclusion, screening for Barrett's esophagus and surveillance in Barrett's subjects have minimal established benefits, but proposed changes in screening practices and innovations in Barrett's esophagus endoscopic surveillance and dysplasia therapy have great promise.

Magnitude and Time-Trends of Post-Endoscopy Esophageal Adenocarcinoma and Post-Endoscopy Esophageal Neoplasia in a Population-Based Cohort Study: The Nordic Barrett’s Esophagus Study

e16046 Background: Esophageal cancer is the sixth most common cause of cancer-related mortality. There are two distinct histological types of esophageal cancer: esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC). In China, ESCC is the major subtype. Higher incidence of EAC is observed in western countries. Liquid biopsy detecting circulating tumor DNA is a non-invasive, real-time and highly sensitive approach that is able to identify and monitor the genetic mutations in tumor. Methods: In this study, we collected 490 Chinese esophageal cancer patients from 2018-2022 and characterized the mutational landscape of esophageal tumor tissue and circulating tumor DNA by whole exome sequencing or deep sequencing of targeted gene panel. The consistency of genetic alteration between tumor and ctDNA was also explored. Results: A total of 176 patients with plasma and 345 patients with cancer tissue were analyzed, among them, 31 patients had both ctDNA and tissue biopsy data. 277 genes with 1257 mutations were identified from plasma samples of 176 patients. The top frequently mutated genes were TP53 (89.1%), KMT2D (24.0%), SYNE1 (14.9%), NOTCH1 (14.3%), EP300 (13.7%), LRP1B (13.7%) and ZNF750 (10.3%). The mutation rates of these genes between ctDNA and tissue biopsy (N = 31 patients) were in concordance by Fisher's exact test (P &gt; 0.05). Most frequent mutations were found in TP53 gene, which account for 89.1% of total plasma samples and 90.4% of tumor tissues. KMT2D gene mutations were detected in 24% of patients which encode histone methyltransferase that methylates the Lys-4 position of histone H3 and regulates transcriptional activation, indicating epigenetic regulation might be involved in the pathogenesis of esophageal cancer. Functional enrichment analysis was performed including Gene Ontology (GO) and KEGG analysis across all the three domains, Biological process, Molecular Function, and Cellular component. The KEGG terms with the highest enrichment score were PI3K−Akt signaling pathway, which is a key driver in carcinogenesis. In addition, we didn’t observe the mutually exclusive mutation or co-occurrence pattern of any gene pairs in our cohort. Conclusions: We demonstrated the utility of liquid biopsy to draw a ctDNA mutation profiling of esophageal cancer in Chinese patients. Genetic mutations identified from ctDNA showed consistency with mutations from tumor tissue.

Introduction Esophageal adenocarcinoma incidence has increased significantly despite surveillance endoscopy for Barrett’s esophagus (BE) and gastric acid supression medications. This prospective, cohort study’s aims were to determine the long-term efficacy of proton-pump inhibitors twice daily (PPI-BID) with cryotherapy (CRYO) for complete ablation of BE. Materials and Methods Consecutive BE patients were managed with a PPI-BID, CRYO ablation, follow-up protocol. Primary outcomes were to determine complete ablation rate of intestinal metaplasia (IM) or dysplasia/carcinoma, and factors affecting recurrence. Results Sixty-two patients were enrolled: advanced disease (11%), low-grade or indefinite dysplasia (26%), non-dysplastic BE (63%). In 58 completing CRYO, eradication was confirmed in 100% on surveillance endoscopy. Adverse events (5%) were minor (mild pain 4%). IM recurred in 9% after a mean of 52 months, all successfully re-ablated. No second recurrence occurred. The primary predictor of recurrence was noncompliance with PPI-BID. BE or cardia IM recurred in 35% of those taking proton pump inhibitors once daily or less compared with 0% in those on PPI-BID or dexlansoprazole daily (p<.001). Conclusions Minimizing acid reflux with at least PPI-BID combined with CRYO ablation appears to be the optimal cost-effective and safe BE treatment for any stage to minimize progression to adenocarcinoma by addressing both the stimulus that causes BE and the presence of goblet cells. KEY MESSAGES Endoscopic surveillance of Barrett’s esophagus (BE) has not made any clear impact on incidence of or mortality from esophageal adenocarcinoma. After cost-effective, safe cryoablation of BE, continued effective acid-reflux control with high-dose proton pump inhibitors is critical to minimize recurrence or progression. Risk factors and costs will define methods and frequency of limited surveillance after ablation of BE.

Risk factors contributing to more than 10-fold increase in esophageal cancer in the last 50 years remain underexplored. We aim to examine the associations of sleep behaviors with esophageal adenocarcinoma (EAC) and squamous cell carcinoma (ESCC). We prospectively assessed the associations between sleep behaviors (chronotype, duration, daytime napping, daytime sleepiness, snoring, and insomnia) and EAC and ESCC risk in 393,114 participants in the UK Biobank (2006-2016). Participants with 0, 1, and ≥2 unhealthy behaviors, including sleep <6 or >9 h/d, daytime napping, and usual daytime sleepiness were classified as having a good, intermediate, and poor sleep. For EAC, we also examined interactions with polygenic risk score (PRS). Cox models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). We documented 294 incident EAC and 95 ESCC. Sleep >9 h/d (HR, 2.05; 95% CI, 1.18-3.57) and sometimes daytime napping (HR, 1.36; 95% CI, 1.06-1.75) were individually associated with increased EAC risk. Compared with individuals with good sleep, those with intermediate sleep had a 47% (HR, 1.47; 95% CI, 1.13-1.91) increased EAC risk, and those with poor sleep showed an 87% (HR, 1.87; 95% CI, 1.24-2.82) higher risk (Ptrend < 0.001). The elevated risks for EAC were similar within strata of PRS (Pinteraction = 0.884). Evening chronotype was associated with elevated risk of ESCC diagnosed after 2 years of enrollment (HR, 2.79; 95% CI, 1.32-5.88). Unhealthy sleep behaviors were associated with an increased risk of EAC, independent of genetic risk. Sleep behaviors may serve as modifiable factors for the prevention of EAC.

Early-onset adenocarcinomas of different sites are increasing in high-income countries, data on esophagogastric adenocarcinoma are sparse. We performed a Swedish population-based cohort study over 1993-2019 to delineate differences in incidence and survival in early-onset (age 20-54 years) compared to later-onset (55-99 years) esophageal, cardia, and non-cardia gastric adenocarcinoma. Temporal incidence trends were quantified as annual percentage changes (APC) and survival differences as excess mortality rate ratios (EMRR) using Poisson regression and including 95% confidence intervals (CI). Among 27,854 esophagogastric adenocarcinoma patients, 2576 were early-onset whereof 470 were esophageal, 645 were cardia, and 1461 were non-cardia gastric. Except non-cardia gastric, the male predominance was larger in early- compared to later-onset disease. Advanced stage and signet ring cell morphology were more common among early-onset patients. Early- and later-onset APC estimates were comparable and esophageal adenocarcinoma incidence increased, cardia remained stable, and non-cardia gastric decreased. Early-onset patients had better survival than later-onset, which was amplified when adjusting for prognostic factors including stage (adjusted EMRR 0.73 [95% CI 0.63-0.85] in esophageal, 0.75 [95% CI 0.65-0.86] in cardia, and 0.67 [95% CI 0.61-0.74] in non-cardia gastric adenocarcinoma). The early-onset survival advantage was more pronounced in localized stages 0-II (all sites) and women (esophageal and non-cardia gastric). We found no major differences in incidence trends comparing early- and later-onset esophagogastric adenocarcinoma. Despite unfavorable prognostic features, early-onset esophagogastric adenocarcinoma survival was better than later-onset, particularly in localized stages and women. Our findings suggest delayed diagnosis in younger individuals and especially men.

Abstract Introduction: Esophageal cancer causes sixth most cancer-related morbidity and mortality worldwide, with a survival rate of &amp;lt;20%. Incidence of esophageal adenocarcinoma (EA) subtype has been rising (&amp;gt;60%) in North America. Systemic docetaxel-based triplet chemotherapy represents the best standard of care, approx. 60% of patients showcasing innate chemo-resistance or developing acquired chemo-resistance. 3D organoids provide a robust and heterogeneous cell source but lack the stromal microenvironment. We established a high-fidelity, stromal-inclusive tumor-on-chip platform expanding on tumor heterogeneity with micro-physiological relevance and flexible complexity. Methods: A total of 8 (4 chemo-sensitive and 4 chemo-resistant) treatment naïve patient-derived organoids (PDOs) and matched fibroblasts were selected to develop syngeneic human esophageal microtissues (tumor and adjacent) on commercially available (Emulate), compartmentalized, porous polydimethylsiloxane (PDMS) membrane-based microfluidic device. Chips accommodate organoids-derived epithelial cells at the upper mucosal channel and matched fibroblasts at the bottom stromal channel. 3D-microtissue development on the chip and treatment-induced cytotoxicity were examined for up to 11 days. We followed the FLOT (docetaxel, oxaliplatin, and 5-fluorouracil; 1:1.7:52) based chemotherapy regime on the chip and evaluated the recapitulation of patient-specific response. Epithelial barrier integrity, adenocarcinoma-associated cellular proteins, and level of cyfra 21-1 (circulating tumor biomarker) were determined on-chip grown microtissues. Results: Real-time brightfield microscopic observations revealed that the EA chips manifest mucin production, adequate tissue tight epithelial barriers, and distinct morphological characteristics that emerged with adenocarcinoma progression. Presence of pleomorphic cells (multiple shapes and sizes), establishment of tight epithelial barriers and formation of mature microvilli was observed via electron microscopy. Patient specific tumor tissue growth were observed for maximum 12 days under a physiologically relevant media flow. Perfusion of pharmacokinetically pertinent doses of triplet chemotherapeutic compounds performed through the stromal channel and each chip recapitulated level of chemosensitivity observed in the patient. Fluorescent probes and LDH assay also demonstrated patient-specific chemo response. Confocal imaging revealed differential expression of proliferation (ki67), epithelial (CK7, E-cadherin), and mesenchymal (Vimentin) markers in each patient-derived chip. Conclusions: Human esophageal adenocarcinoma-on-a-chip is a novel, most human-relevant biomimetic platform built on a microfluidic chip and a potential alternative to inadequate pre-clinical animal models in the future. Citation Format: Sanjima Pal, Elee Shimshoni, Salvador Flores-Torres, Julie Bérubé, Kulsum Tai, Iris Kong, Betty Giannias, Sean Hall, Nicholas Bertos, Veena Sangwan, Donald E. Ingber, Lorenzo Ferri. Esophageal adenocarcinoma-on-a-chip; modeling patient specific disease progression and a step towards functional precision oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 168.

Abstract Background: While the incidence of esophageal adenocarcinoma (EAC) is rapidly increasing, the 5-year survival rate of this disease remains poor at less than 25%, with a substantial number of patients exhibiting inherent or acquired resistance to chemotherapy. Circulating tumor DNA (ctDNA) isolated from liquid biopsies of EAC patients holds clinical biomarker potential in this disease, but our understanding of how chemotherapy affects ctDNA release remains limited. Methods: In order to study the impact of cancer treatment on ctDNA emission in vitro, we first sought to establish a chemo-resistant model of EAC. As such, the EAC cell line OE19 was exposed to discontinuous cisplatin treatments for three months in order to establish drug resistance. Following this, established chemo-resistant OE19 cells and parental (chemo-sensitive) OE19 cells were exposed to five daily cisplatin treatments, and cell culture supernatant was collected every day throughout treatment. ctDNA was subsequently isolated from cell culture supernatant and quantified by Qubit fluorometer dsDNA HS assay. ctDNA quantities were additionally assessed by droplet digital PCR (ddPCR) assay using primers and probes targeting the TP53 N310K mutation in the OE19 cell line. Finally, ctDNA fragment lengths were analyzed using the Agilent Bioanalyzer 2100. Results: A chemo-resistant model of the OE19 cell line was established, as exemplified by marked morphological changes in the cells and significantly increased cell viability determined by CCK8 assay after 48-hour treatments of various doses of cisplatin (p&amp;lt;0.05). ctDNA levels, as measured by both Qubit fluorometer and mutant copies detected by ddPCR assay, increased after chemotherapy treatment for both chemo-sensitive and resistant cells. Notably, ctDNA emission was higher with larger amounts cell death, with chemo-sensitive cells emitting significantly higher levels of ctDNA compared to chemo-resistant cells throughout treatment (p&amp;lt;0.05). Fragmentomics analysis revealed ctDNA peaks corresponding to apoptosis (~167 bp) and necrosis (~10,000 bp). Moreover, chemotherapy treatment caused a shift in average fragment size, with larger fragments being observed during chemotherapy treatment in both chemo-sensitive and resistant cells. Conclusion: This study reveals that in vitro cancer models can be used to successfully study ctDNA emission during pre-clinical drug analyses. ctDNA release was found to be correlated to cytotoxicity and cell death, providing us with valuable insight into how clinical liquid biopsy data should be interpreted. Finally, fragment size analysis of ctDNA reveals a potential novel biomarker for treatment response in cancer patients. Citation Format: Alexandra Bartolomucci, Sarah Tadhg Ferrier, Thupten Tsering, Xin Su, Jonathan Cools-Lartigue, Julia V. Burnier. Characterizing circulating tumor DNA release kinetics and fragment length in a chemotherapy resistant model of esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6700.

Abstract Background: The incidence of esophageal adenocarcinoma (EAC) has increased more than six-fold over the past three decades and continues to rise in the Western world. The 5-year survival rate for EAC patients is less than 20% which underscores the need to better understand the underlying mechanisms to identify new therapeutic approaches. This study aimed at investigating the potential role of APE1 in regulating SMAD3 and promoting EAC progression. Methods and Results: Western blot data showed that APE1 and SMAD3 were highly expressed in EAC cell lines. APE1 silencing reduced SMAD3 nuclear expression and downregulated its downstream targets SERPINE1 and c-myc. These results were confirmed by immunofluorescence staining showing loss of nuclear accumulation of SMAD3 after APE1 knockdown. Mechanistically, immunoprecipitation and proximity ligation assays revealed a direct binding between APE1 and SMAD3 in the nucleus. Further investigation showed that APE1 binds to the C-terminal MH2 domain of SMAD3, and this binding protects SMAD3 from ubiquitin mediated proteasomal degradation by blocking its interaction with the RING finger protein, ROC1. Interestingly, APE1-redox-specific inhibition (APX2009) downregulated SMAD3 expression and the APE1 redox-deficient mutant (C65A) disrupted APE1-SMAD3 binding indicating that this regulation depends on APE1 redox activity. Conclusion: Our findings establish a role of APE1 in regulating SMAD3 in EAC. These findings provide a potential therapeutic approach for the treatment of EAC by the pharmacological inhibition of APE1. Citation Format: Farah Ballout, Heng Lu, Dunfa Peng, Wael El-Rifai. APE1 protects SMAD3 against ROC1 ubiquitin mediated degradation in esophageal adenocarcinoma cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3964.

Abstract The incidence of esophageal adenocarcinoma (EAC) has increased rapidly over the past four decades. Chronic gastroesophageal reflux disease (GERD), where acidic bile salts (ABS) abnormally refluxate into the esophagus, is the leading risk factor for the development of a metaplastic condition known as Barrett’s esophagus (BE) and its progression to EAC. We used 3D organotypic culture, mouse and human tissue samples to assess the role of ABS in Epithelial-to-Mesenchymal Transition (EMT) in EAC. Analysis of public databases revealed significant enrichment of EMT signaling in EAC progression. RNA-seq analysis of EAC cells showed activation of EMT pathway in response to ABS exposure. ABS induced multiple characteristics of the EMT process, such as downregulation of E-cadherin, upregulation of Vimentin, activation of ß-catenin and EMT-transcription factors (EMT-TFs), cell morphological changes, and enhancement of cell migration and invasion capabilities. Mechanistically, we discovered that ABS induced E-cadherin cleavage via MMP14 proteolytic cascade. APE1 silencing, or APE1-redox-specific inhibitor (E3330), abrogated the ABS-induced EMT process and signaling by downregulating MMP14. Furthermore, APE1 and MMP14 co-expression levels were inversely correlated with E-cadherin expression in gastroesophageal junctions of human EAC tissues, and the L2-IL1ß transgenic mouse model of BE/EAC. EAC patients with high APE1 and EMT signatures had worse relapse free survival than those with low signature. In a summary, this study demonstrates the role of ABS in promoting EMT via the redox-sensitive signaling axis of APE1/MMP14/E-cadherin/ß-catenin. Pharmacological inhibition of APE1-redox function could be a potential therapeutic approach to effectively reduce the risk of Barrett’s carcinogenesis. Citation Format: Heng Lu, Longlong Cao, Farah Ballout, Abbes Belkhiri, Dunfa Peng, Lei Chen, Mohammed Soutto, Oliver McDonald, Alexander Zaika, Jianwen Que, Wael El-Rifai. Gastroesophageal reflux disease promotes E-cadherin cleavage and activates EMT via APE1-redox function in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1232.