Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

Palles, Claire; Chegwidden, Laura; Li, Xinzhong; Findlay, John M.; Farnham, Garry; Castro-Giner, Francesc; Peppelenbosch, Maikel P.; Kováč, Michal; Adams, Claire; Prenen, Hans; Briggs, Sarah; Harrison, Rebecca; Sanders, Scott; MacDonald, David; Haigh, Chris; Tucker, Art; Love, Sharon; Nanji, Manoj; Decaestecker, John; Ferry, David; Rathbone, B. J.; Hapeshi, Julie; Barr, Hugh; Martin, Paul; Watson, Peter; Zietek, Barbara; Maroo, Neera; Underwood, Tim; Boulter, Lisa; McMurtry, Hugh; Monk, David; Patel, Praful; Ragunath, Krish; Dulaimi, David Al; Murray, Iain A.; Koss, K; Veitch, Andrew; Trudgill, Nigel; Nwokolo, Chuka U.; Rembacken, Björn; Atherfold, Paul; Green, Elaine; Ang, Yeng; Kuipers, Ernst J.; Chow, Wu; Paterson, S. K.; Kadri, Sudarshan; Beales, Ian; Grimley, Charles; Mullins, Paul D.; Beckett, Conrad; Farrant, Mark; Dixon, Andrew; Kelly, Sean G.; Johnson, Matthew E.; Wajed, S; Dhar, Anjan; Sawyer, Elinor J.; Roylance, Rebecca; Onstad, Lynn; Gammon, Marilie D.; Corley, Douglas A.; Shaheen, Nicholas J.; Bird, Nigel C.; Hardie, Laura J.; Reid, Brian J.; Ye, Weimin; Liu, Geoffrey; Romero, Yvonne; Bernstein, Leslie; Wu, Anna H.; Casson, Alan G.; Fitzgerald, Rebecca C.; Whiteman, David C.; Risch, Harvey A.; Levine, David; Vaughan, Tom L.; Verhaar, Auke P.; Brande, Jan Van den; Toxopeus, Eelke; Spaander, Manon; Wijnhoven, Bas P. L.; Laan, Luc J. W. van der; Krishnadath, Kausilia K.; Wijmenga, Cisca; Trynka, Gosia; McManus, Ross; Reynolds, John V.; O’Sullivan, Jacintha; MacMathúna, Padraic; McGarrigle, Sarah A.; Kelleher, Dermot; Vermeire, Séverine; Cleynen, Isabelle; Bisschops, Raf; Tomlinson, Ian; Jankowski, Janusz

doi:10.1053/j.gastro.2014.10.041

Cited by 91 publications

(99 citation statements)

References 49 publications

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“…BARX1 is an important repressor of the Wnt signaling pathway during development (discussed above). In addition, TBX5, a transcription factor that was identified in the largest GWAS to date (62), is a key regulator of limb development through the regulation of the expression of Wnt ligands (83). The third GWAS also identified a locus near GDF7, a member of the BMP pathway that is interesting in the light of the potential role of BMP signaling in the development of Barrett's esophagus discussed below.…”

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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Section: Esophageal Epithelial Pathophysiology the Development Of Bamentioning

confidence: 99%

Section: Esophageal Epithelial Pathophysiology the Development Of Bamentioning

confidence: 99%

Esophageal development and epithelial homeostasis

Rosekrans

Baan

Muncan

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…20 Recent large-scale genomewide association studies () have provided comprehensive assessments of genetic susceptibility to BE and OA. [21][22][23][24][25] Novel associations have been identified with variants in or near several transcription factors implicated in embryonic oesophageal development, a transcriptional coactivator and the human leucocyte antigen (HLA) region. It remains likely, however, that additional loci that did not satisfy the commonly used, stringent statistical threshold ( p<5×10 −8 ) may be involved in modifying disease risk.…”

Section: Significance Of This Studymentioning

confidence: 99%

“…Recent large-scale GWAS have provided comprehensive assessments of inherited genetic susceptibility to BE and EA [24, 25, 26, 27, 28]. Novel associations have been identified with variants in or near several transcription factors implicated in embryonic esophageal development, a transcriptional co-activator, and the human leukocyte antigen (HLA) region.…”

Section: Introductionmentioning

confidence: 99%

Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma

Buas

Johnson

et al. 2016

Gut

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Esophageal adenocarcinoma (EA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation, operating downstream of disease-associated exposures, is considered an important contributor to EA pathogenesis. Several risk factors have been identified for EA and its precursor, Barrett’s esophagus (BE), including symptomatic reflux, obesity, and smoking. The role of inherited genetic susceptibility remains an area of active investigation. To explore whether germline variation related to inflammatory processes influences susceptibility to BE/EA, we used data from a genome-wide association study (GWAS) of 2,515 EA cases, 3,295 BE cases, and 3,207 controls. Our analysis included 7,863 single nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signaling, oxidative stress, human leukocyte antigen, and NFκB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. We identified a significant signal for the COX pathway in relation to BE risk (P=0.0059, FDR q=0.03), and in gene-level analyses found an association with MGST1 (microsomal glutathione-S-transferase 1; P=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Of these, four were subsequently confirmed (P<5.5 × 10−5) in a meta-analysis encompassing an independent set of 1,851 BE cases and 3,496 controls. Three of these SNPs (rs3852575, rs73112090, rs4149204) were associated with similar elevations in EA risk. This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/EA, and suggests that variants in MGST1 influence disease susceptibility.

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“…To validate these findings, Palles et al [5] performed a GWAS to identify variants associated with BE and further analyzed promising variants identified by BEACON by genotyping 10,158 patients with BE and 21,062 controls. As a result, 2 SNPs not previously associated with BE were reported: rs3072 (2p24.1; OR = odds ratio = 1.14; 95% CI: 1.09-1.18; p = 1.8 × 10− 11 ) and rs2701108 (12q24.21; OR = 0.90; 95% CI: 0.86-0.93; p = 7.5 × 10− 9 ).…”

Section: Esophageal Adenocarcinomamentioning

confidence: 99%

Genetic Variations in Esophageal Cancer

Qian¹,

Fang²

2015

Gastrointest Tumors

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Background: Esophageal cancer is one of the most prevalent cancers worldwide, and occurs at a relatively high frequency in China and other Asian countries. The etiology of esophageal cancer remains unclear, making its early diagnosis and treatment difficult. Summary: In recent decades, efforts using candidate gene approaches have been made to identify genetic susceptibility factors for esophageal cancer in a series of genome-wide association studies. Here, we review the latest progress in research on genetic variations in esophageal cancer cases. Key Message: Genetic variations partially account for esophageal cancer incidence and mortality rates. A comparative genomic analysis of esophageal squamous cell carcinomas and esophageal adenocarcinomas suggests little overlap genetically. Current integrated studies using high-throughput approaches have unmasked a number of novel genetic lesions in both esophageal cancer and its precursor lesions, although distinct results obtained from different regions and cohorts remain to be investigated. Practical Implications: Pooled analyses of genome-wide association studies should be conducted to establish unique susceptibility loci for specific districts and nationalities. Meanwhile, the identification of ‘driver mutations' or mutations associated with prognosis in long-term follow-up studies is critical for the development of therapeutic and prognostic strategies.

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Polymorphisms Near TBX5 and GDF7 Are Associated With Increased Risk for Barrett’s Esophagus

Cited by 91 publications

References 49 publications

Esophageal development and epithelial homeostasis

Esophageal development and epithelial homeostasis

Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma

Genetic Variations in Esophageal Cancer

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