A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus

Levine, David; Ek, Weronica E.; Zhang, Rui; Liu, Xinxue; Onstad, Lynn; Sather, Cassandra L.; Lao‐Sirieix, Pierre; Gammon, Marilie D.; Corley, Douglas A.; Shaheen, Nicholas J.; Bird, Nigel C.; Hardie, Laura J.; Murray, Liam; Reid, Brian J.; Chow, Wong Ho; Risch, Harvey A.; Nyrén, Olof; Ye, Weimin; Liu, Geoffrey; Romero, Yvonne; Bernstein, Leslie; Wu, Anna H.; Casson, Alan G.; Chanock, Stephen J.; Harrington, Patricia; Caldas, Isabel; Debiram–Beecham, Irene; Caldas, Carlos; Hayward, Nicholas K.; Pharoah, Paul D.P.; Fitzgerald, Rebecca C.; MacGregor, Stuart; Whiteman, David C.; Vaughan, Thomas L.

doi:10.1038/ng.2796

Cited by 176 publications

(224 citation statements)

References 39 publications

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“…Th e overall diagnostic yield was 20% ( 43 ). Single-nucleotide polymorphisms on gene loci, which may confer increased susceptibility to BE development, have recently been described (44)(45)(46)(47).…”

Section: Summary Of Evidencementioning

confidence: 99%

ACG Clinical Guideline: Diagnosis and Management of Barrett’s Esophagus

Shaheen

Falk

Iyer

et al. 2016

American Journal of Gastroenterology

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Recent population studies suggest that gastroesophageal refl ux disease (GERD) is increasing in prevalence, both in the United States and worldwide ( 1,2 ). Th e diagnosis of GERD is associated with a 10-15% risk of Barrett's esophagus (BE), a change of the normal squamous epithelium of the distal esophagus to a columnar-lined intestinal metaplasia (IM). Risk factors associated with the development of BE include long-standing GERD, male gender, central obesity ( 3 ), and age over 50 years ( 4,5 ). Th e goal of a screening and surveillance program for BE is to identify individuals at risk for progression to esophageal adenocarcinoma (EAC), a malignancy that has been increasing in incidence since the 1970s ( 6,7 ).Th e purpose of this guideline is to review the defi nition and epidemiology of BE, available screening modalities for BE detection, rationale and methods for surveillance, and available treatment modalities including medical, endoscopic, and surgical techniques. In order to evaluate the level of evidence and strength of recommendations, we used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system ( 8 ). Th e level of evidence ranged from "high" (implying that further research was unlikely to change the authors' confi dence in the estimate of the eff ect) to "moderate" (further research would be likely to have an impact on the confi dence in the estimate of eff ect) to "low" (further research would be expected to have an important impact on the confi dence in the estimate of the eff ect and would be likely to change the estimate) or "very low" (any estimate of eff ect is very uncertain). Th e strength of a recommendation was graded as "strong" when the desirable eff ects of an intervention clearly outweighed the undesirable eff ects and as "conditional" when there was uncertainty about the tradeoff s. We used meta-analyses or systematic reviews when available, followed by clinical trials and cohort and case-control studies. In order to determine the level Barrett's esophagus (BE) is among the most common conditions encountered by the gastroenterologist. In this document, the American College of Gastroenterology updates its guidance for the best practices in caring for these patients. These guidelines continue to endorse screening of high-risk patients for BE; however, routine screening is limited to men with refl ux symptoms and multiple other risk factors. Acknowledging recent data on the low risk of malignant progression in patients with nondysplastic BE, endoscopic surveillance intervals are attenuated in this population; patients with nondysplastic BE should undergo endoscopic surveillance no more frequently than every 3-5 years. Neither routine use of biomarker panels nor advanced endoscopic imaging techniques (beyond high-defi nition endoscopy) is recommended at this time. Endoscopic ablative therapy is recommended for patients with BE and high-grade dysplasia, as well as T1a esophageal adenocarcinoma. Based on recent level 1 evidence, endoscopic ablative therapy is ...

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Section: Summary Of Evidencementioning

confidence: 99%

ACG Clinical Guideline: Diagnosis and Management of Barrett’s Esophagus

Shaheen

Falk

Iyer

et al. 2016

American Journal of Gastroenterology

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“…Increased Wnt signaling could play a role in the development of intestinal metaplasia since Wnt signaling needs to be repressed to allow the development of normal esophageal epithelium and the Wnt pathway is the major pathway in the specification of the intestinal stem cell phenotype. The potential for interaction with the Wnt signaling pathway is something FOXP1 has in common with the second transcription factor with an association with Barrett's esophagus identified in the same GWAS (38).…”

Section: Esophageal Epithelial Pathophysiology the Development Of Bamentioning

confidence: 99%

“…A subsequent large GWAS identified a further two transcriptional regulators with a key role in development in the risk to develop Barrett's esophagus (38). The first is FOXP1.…”

Section: Esophageal Epithelial Pathophysiology the Development Of Bamentioning

confidence: 99%

“…Genomewide association studies (GWAS) that examined genetic predisposition to the development of Barrett's esophagus have implicated several pathways with a role in the development of the esophagus (38,62,81). One of the most significant associations with the development of Barrett's esophagus found in the first large GWAS is a single-nucleotide polymorphism (SNP) that is very close to FOXF1 (81), the mesenchymally expressed Hedgehog target that acts upstream of BMP4 during development (see above).…”

Section: Esophageal Epithelial Pathophysiology the Development Of Bamentioning

confidence: 99%

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Esophageal development and epithelial homeostasis

Rosekrans

Baan

Muncan

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Rosekrans SL, Baan B, Muncan V, van den Brink GR. Esophageal development and epithelial homeostasis. Am J Physiol Gastrointest Liver Physiol 309: G216 -G228, 2015. First published July 2, 2015; doi:10.1152/ajpgi.00088.2015.-The esophagus is a relatively simple organ that evolved to transport food and liquids through the thoracic cavity. It is the only part of the gastrointestinal tract that lacks any metabolic, digestive, or absorptive function. The mucosa of the adult esophagus is covered by a multilayered squamous epithelium with a remarkable similarity to the epithelium of the skin despite the fact that these tissues originate from two different germ layers. Here we review the developmental pathways involved in the establishment of the esophagus and the way these pathways regulate gut-airway separation. We summarize current knowledge of the mechanisms that maintain homeostasis in esophageal epithelial renewal in the adult and the molecular mechanism of the development of Barrett's metaplasia, the precursor lesion to esophageal adenocarcinoma. Finally, we examine the ongoing debate on the hierarchy of esophageal epithelial precursor cells and on the presence or absence of a specific esophageal stem cell population. Together the recent insights into esophageal development and homeostasis suggest that the pathways that establish the esophagus during development also play a role in the maintenance of the adult epithelium. We are beginning to understand how reflux of gastric content and the resulting chronic inflammation can transform the squamous esophageal epithelium to columnar intestinal type metaplasia in Barrett's esophagus. esophagus; development; homeostasis; stem cell; endoderm THE WORD ESOPHAGUS IS DERIVED from the Greek words ε (oisein, to carry) and ␣␥ε (phagein, to eat). This description fits well with the functional role of the esophagus that mainly serves to "carry food" into the stomach. From the pharyngoesophageal junction, the esophagus passes through the mediastinum and diaphragm and connects to the cardia of the stomach at the gastroesophageal junction or Z-line. The pharyngoesophageal and gastroesophageal junctions anatomically overlap with the upper and lower esophageal sphincters. Both sphincters are closed except during swallowing to assure a unidirectional flow of esophageal content toward the stomach and to prevent reflux of gastric content into the esophagus. The relatively simple histology of the esophageal epithelium corresponds with the fact that the esophagus has no role other than to pass food through the thorax to the stomach. It does not play a known digestive, endocrine, or metabolic role and the epithelium consists of a simple stratified squamous epithelium, which provides a good protective layer against the unmodified food stream on its way to the stomach. Despite the perhaps somewhat prosaic functional role of the esophagus compared with other organs in the body, we feel that it is essential to gain a better understanding of the mechanisms that regulate normal esophageal homeo...

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“…Furthermore, recent genome-wide association studies have demonstrated that there might be a genetic base in development of OAC. 32,33 In the future, a multidisciplinary approach to patients with BO may be used, incorporating endoscopic, patient, genetic and biomolecular characteristics to tailor surveillance and to select patients who would benefit from prophylactic treatment of their BO.…”

Section: Presence Of Lgdmentioning

confidence: 99%

Endoscopic risk factors for neoplastic progression in patients with Barrett’s oesophagus

2016

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Barrett's oesophagus is a precursor lesion for oesophageal adenocarcinoma, which generally has a poor prognosis. Patients diagnosed with Barrett's oesophagus therefore undergo regular endoscopic surveillance to detect neoplastic lesions at a curable stage. The efficacy of endoscopic surveillance of Barrett's oesophagus patients is, however, hampered by difficulties to detect early neoplasia endoscopically, biopsy sampling error, inter-observer variability in histological assessment and the relatively low overall progression rate. Efficacy and cost-effectiveness of Barrett's surveillance may be improved by using endoscopic and clinical characteristics to risk-stratify Barrett's patients to high-and low-risk categories. Recent national and international surveillance guidelines have incorporated Barrett's length and presence of low-grade dysplasia in the advised surveillance intervals. In this review we will discuss endoscopic characteristics that may be associated with neoplastic progression in Barrett's oesophagus and that may be used to tailor surveillance in Barrett's patients.

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A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett's esophagus

Cited by 176 publications

References 39 publications

ACG Clinical Guideline: Diagnosis and Management of Barrett’s Esophagus

ACG Clinical Guideline: Diagnosis and Management of Barrett’s Esophagus

Esophageal development and epithelial homeostasis

Endoscopic risk factors for neoplastic progression in patients with Barrett’s oesophagus

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