Unraveling the Pathogenesis of Barrett's Esophagus and Esophageal Adenocarcinoma: the "omics" Era

Overview

Journal Front Oncol

Specialty Oncology

Date 2025 Feb 14

PMID 39950103

Authors

Alberto Barchi

Giuseppe DellAnna

Luca Massimino

Francesco Vito Mandarino

Edoardo Vespa

Edi Viale

Sandro Passaretti

Vito Annese

Alberto Malesci

Silvio Danese

Federica Ungaro

Affiliations

Soon will be listed here.

Abstract

Barrett's esophagus (BE) represents a pre-cancerous condition that is characterized by the metaplastic conversion of the squamous esophageal epithelium to a columnar intestinal-like phenotype. BE is the consequence of chronic reflux disease and has a potential progression burden to esophageal adenocarcinoma (EAC). The pathogenesis of BE and EAC has been extensively studied but not completely understood, and it is based on two main hypotheses: "transdifferentiation" and "transcommitment". Omics technologies, thanks to the potentiality of managing huge amounts of genetic and epigenetic data, sequencing the whole genome, have revolutionized the understanding of BE carcinogenesis, paving the way for biomarker development helpful in early diagnosis and risk progression assessment. Genomics and transcriptomics studies, implemented with the most advanced bioinformatics technologies, have brought to light many new risk loci and genomic alterations connected to BE and its progression to EAC, further exploring the complex pathogenesis of the disease. Early mutations of the TP53 gene, together with late aberrations of other oncosuppressor genes (SMAD4 or CKND2A), represent a genetic driving force behind BE. Genomic instability, nonetheless, is the central core of the disease. The implementation of transcriptomic and proteomic analysis, even at the single-cell level, has widened the horizons, complementing the genomic alterations with their transcriptional and translational bond. Increasing interest has been gathered around small circulating genetic traces (circulating-free DNA and micro-RNAs) with a potential role as blood biomarkers. Epigenetic alterations (such as hyper or hypo-methylation) play a meaningful role in esophageal carcinogenesis as well as the study of the tumor micro-environment, which has led to the development of novel immunological therapeutic options. Finally, the esophageal microbiome could be the protagonist to be investigated, deepening our understanding of the subtle association between the host microbiota and tumor development.

References

Stachler M, Camarda N, Deitrick C, Kim A, Agoston A, Odze R . Detection of Mutations in Barrett's Esophagus Before Progression to High-Grade Dysplasia or Adenocarcinoma. Gastroenterology. 2018; 155(1):156-167. PMC: 6035092. DOI: 10.1053/j.gastro.2018.03.047. View

Chettouh H, Mowforth O, Galeano-Dalmau N, Bezawada N, Ross-Innes C, MacRae S . Methylation panel is a diagnostic biomarker for Barrett's oesophagus in endoscopic biopsies and non-endoscopic cytology specimens. Gut. 2017; 67(11):1942-1949. PMC: 6176521. DOI: 10.1136/gutjnl-2017-314026. View

Ayazi S, Hagen J, Chan L, DeMeester S, Lin M, Ayazi A . Obesity and gastroesophageal reflux: quantifying the association between body mass index, esophageal acid exposure, and lower esophageal sphincter status in a large series of patients with reflux symptoms. J Gastrointest Surg. 2009; 13(8):1440-7. PMC: 2710497. DOI: 10.1007/s11605-009-0930-7. View

Zhou J, Shrestha P, Qiu Z, Harman D, Teoh W, Al-Sohaily S . Distinct Microbiota Dysbiosis in Patients with Non-Erosive Reflux Disease and Esophageal Adenocarcinoma. J Clin Med. 2020; 9(7). PMC: 7408827. DOI: 10.3390/jcm9072162. View

Alvi M, Liu X, ODonovan M, Newton R, Wernisch L, Shannon N . DNA methylation as an adjunct to histopathology to detect prevalent, inconspicuous dysplasia and early-stage neoplasia in Barrett's esophagus. Clin Cancer Res. 2012; 19(4):878-88. PMC: 4998953. DOI: 10.1158/1078-0432.CCR-12-2880. View

Peters Y, Honing J, Kievit W, Kestens C, Pestman W, Nagtegaal I . Incidence of Progression of Persistent Nondysplastic Barrett's Esophagus to Malignancy. Clin Gastroenterol Hepatol. 2018; 17(5):869-877.e5. DOI: 10.1016/j.cgh.2018.08.033. View

Salam I, Hussain S, Mir M, Dar N, Abdullah S, Siddiqi M . Aberrant promoter methylation and reduced expression of p16 gene in esophageal squamous cell carcinoma from Kashmir valley: a high-risk area. Mol Cell Biochem. 2009; 332(1-2):51-8. DOI: 10.1007/s11010-009-0173-7. View

Klaver E, Bureo Gonzalez A, Mostafavi N, Mallant-Hent R, Duits L, Baak B . Barrett's esophagus surveillance in a prospective Dutch multi-center community-based cohort of 985 patients demonstrates low risk of neoplastic progression. United European Gastroenterol J. 2021; 9(8):929-937. PMC: 8498404. DOI: 10.1002/ueg2.12114. View

Iwaya T, Endo F, Takahashi F, Tokino T, Sasaki Y, Nishizuka S . Frequent Tumor Burden Monitoring of Esophageal Squamous Cell Carcinoma With Circulating Tumor DNA Using Individually Designed Digital Polymerase Chain Reaction. Gastroenterology. 2020; 160(1):463-465.e4. DOI: 10.1053/j.gastro.2020.09.035. View

10.

Chen D, Hu Q, Mao C, Jiao Z, Wang S, Yu L . Increased IL-17-producing CD4(+) T cells in patients with esophageal cancer. Cell Immunol. 2011; 272(2):166-74. DOI: 10.1016/j.cellimm.2011.10.015. View

11.

Borgmann M, Quante M . Impact of the Tumor Microenvironment for Esophageal Tumor Development-An Opportunity for Prevention?. Cancers (Basel). 2022; 14(9). PMC: 9100503. DOI: 10.3390/cancers14092246. View

12.

Fassan M, Volinia S, Palatini J, Pizzi M, Baffa R, de Bernard M . MicroRNA expression profiling in human Barrett's carcinogenesis. Int J Cancer. 2010; 129(7):1661-70. PMC: 4303574. DOI: 10.1002/ijc.25823. View

13.

Schulmann K, Sterian A, Berki A, Yin J, Sato F, Xu Y . Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk. Oncogene. 2005; 24(25):4138-48. DOI: 10.1038/sj.onc.1208598. View

14.

Kim E, Im H, Lee J, Cho E, Kim Y, Kim H . Genome-wide and size-based cell-free DNA indices as predictive biomarkers for locally advanced esophageal squamous cell carcinoma treated with preoperative or definitive chemoradiotherapy. Curr Probl Cancer. 2020; 45(3):100685. DOI: 10.1016/j.currproblcancer.2020.100685. View

15.

van der Wel M, Coleman H, Bergman J, Jansen M, Meijer S . Histopathologist features predictive of diagnostic concordance at expert level among a large international sample of pathologists diagnosing Barrett's dysplasia using digital pathology. Gut. 2019; 69(5):811-822. DOI: 10.1136/gutjnl-2019-318985. View

16.

Stein A, Dislich B, Blank A, Guldener L, Kroll D, Seiler C . High intratumoural but not peritumoural inflammatory host response is associated with better prognosis in primary resected oesophageal adenocarcinomas. Pathology. 2016; 49(1):30-37. DOI: 10.1016/j.pathol.2016.10.005. View

17.

Edrisi M, Huang X, Ogilvie H, Nakhleh L . Accurate integration of single-cell DNA and RNA for analyzing intratumor heterogeneity using MaCroDNA. Nat Commun. 2023; 14(1):8262. PMC: 10719311. DOI: 10.1038/s41467-023-44014-3. View

18.

Kaz A, Grady W, Stachler M, Bass A . Genetic and Epigenetic Alterations in Barrett's Esophagus and Esophageal Adenocarcinoma. Gastroenterol Clin North Am. 2015; 44(2):473-89. PMC: 4449457. DOI: 10.1016/j.gtc.2015.02.015. View

19.

Alderson D, Wijnhoven B . Interventions for Barrett's oesophagus and early cancer. Br J Surg. 2016; 103(5):475-6. DOI: 10.1002/bjs.10135. View

20.

Belle C, Lonie J, Brosda S, Barbour A . Tumour microenvironment influences response to treatment in oesophageal adenocarcinoma. Front Immunol. 2023; 14:1330635. PMC: 10753779. DOI: 10.3389/fimmu.2023.1330635. View