Supportive evidence for <scp>FOXP</scp>1,<scp>BARX</scp>1, and <scp>FOXF</scp>1 as genetic risk loci for the development of esophageal adenocarcinoma

Becker, Jéssica; May, Andrea; Gerges, Christian; Anders, Mario; Veits, Lothar; Weise, Katharina; Czamara, Darina; Lyros, Orestis; Manner, Hendrik; Terheggen, Grischa; Venerito, Marino; Noder, Tania; Mayershofer, Rupert; Hofer, Jan-Hinnerk; Karch, Hans‐Werner; Ahlbrand, Constantin J.; Arras, Michael; Hofer, Sebastian J.; Mangold, Elisabeth; Heilmann‐Heimbach, Stefanie; Heinrichs, Sophie K. M.; Hess, Timo; Kießlich, Ralf; Izbicki, Jakob R.; Hölscher, Arnulf H.; Bollschweiler, Elfriede; Malfertheiner, Peter; Lang, Hauke; Moehler, Markus; Lorenz, D.; Müller‐Myhsok, Bertram; Ott, Katja; Schmidt, Thomas; Whiteman, David C.; Vaughan, Thomas L.; Nöthen, Markus M.; Hackelsberger, Andreas; Schumacher, Brigitte; Pech, Oliver; Vashist, Yogesh K.; Vieth, Michael; Weismüller, Josef; Neuhaus, Horst; Rösch, Thomas; Ell, Christian; Gockel, Ines; Schumacher, Johannes

doi:10.1002/cam4.500

Cited by 25 publications

(16 citation statements)

References 11 publications

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“…POU5F1, SOX, BRCA1, FOXP1; Table S5) [50]. Of interest, FOXP1 was identified as a susceptibility locus for EA in our previous report [24], and recently replicated in an independent study [28]. Published eQTL data from a study of gene expression in various brain regions indicated that rs4149203 (and correlated SNPs) may be associated with altered MGST1 expression in cerebellum [50, 51].…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Significance Of This Studymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…Additionally, some reports have shown that rs12100561 ( C14orf143 ), rs2178146 ( FOXF1 ), and rs1050631 ( SLC39A6 ) are associated with increased susceptibility to hepatocellular carcinoma [12], esophageal adenocarcinoma [13], and esophageal squamous-cell carcinoma [14], respectively. However, to our knowledge, few studies have examined associations between polymorphisms and the risk of GC or CRC.…”

Section: Introductionmentioning

confidence: 99%

Genetic polymorphisms are associated with the risk of gastric and colorectal cancers in a Han Chinese population

et al. 2017

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Here, we genotyped eleven single-nucleotide polymorphisms (SNPs) and evaluated their association with the risk of developing gastric cancer (GC) or colorectal cancer (CRC) in 1,790 Han Chinese participants (588 GC patients, 499 CRC patients, and 703 healthy controls). Statistically analysis showed that the “C” allele of rs2689154 in MIPEPP2 was associated with a decreased risk of GC (odds ratio [OR] = 0.81, 95 % confidence interval [CI]: 0.66-0.99, P = 0.041), whereas the “T” allele of rs12615966 in LOC284998 was associated with a 1.29-fold increase in the risk of GC (OR = 1.29, 95% CI: 1.03-1.63, P = 0.029). Additionally, genetic model analyses showed that rs2689154 was associated with a reduced risk of GC under the recessive model (adjusted OR = 0.46, 95% CI: 0.22-0.98, P = 0.037), and rs12615966 in FOXF1 was associated with an increased risk of GC in both the dominant and log-additive models after adjusted for age and gender (adjusted OR = 1.36, 95% CI: 1.02-1.81, P = 0.033; adjusted OR = 1.36, 95% CI: 1.05-1.75, P = 0.018, respectively). We also observed that rs2178146 in FOXF1 was associated with an increased risk of CRC in the recessive model (adjusted OR = 1.90, 95% CI: 1.05-3.45, P = 0.034). Our results confirmed that rs2689154 in MIPEPP2 was significantly decreased GC risk, but rs12615966 in LOC284998 was significantly increased GC risk, and rs2178146 in FOXF1 was associated with increased CRC risk in the Han Chinese population.

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“…GWAS in Europe and the USA have shown that the shared polygenic effects due to many genetic variants with a small effect contribute to the development of EAC [59]. Several significant SNPs are associated with FOXP1, BARX1, FOXF1, CRTC1, CDKN2A and TP53 [60,61,62]. Interestingly, genetic risk variants for common cancers and microRNA-related variants are seemingly not associated with the risk of EAC [63,64].…”

Section: Esophageal Adenocarcinomamentioning

confidence: 99%

Etiology and Prevention of Esophageal Cancer

Yang

Chen

2016

Gastrointest Tumors

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Background: Esophageal cancer (EC) occurs commonly, especially in Asia, and is the sixth leading cause of cancer deaths worldwide. Recently, great progress has been made in research on the etiology and prevention of EC. Summary: The major risk factors for esophageal squamous cell carcinoma (ESCC) are tobacco smoking and alcohol drinking, which act synergistically. Dietary parameters, including dietary carcinogens and insufficiency of micronutrients, could also be important risk factors in certain areas. A common etiological factor for both EC and some other cancers are low levels of intake of fruits and vegetables. With improvements in diet and drinking water in developing countries, the incidence of ESCC decreased. However, in economically well-developed countries, the incidence of esophageal adenocarcinoma (EAC) has markedly increased in the past 40 years. The major etiological factor for EAC is gastroesophageal reflux, which is also an etiological factor for gastric cardia adenocarcinoma (GCA). In certain areas of China, the occurrence of GCA is closely related to ESCC. Susceptibility genes for EC are starting to be discovered, and this may help to identify high-risk groups that have more need for preventive measures. Mitigation of the risk factors, early detection and treatment of precancerous lesions are effective approaches for prevention. Smoking cessation, avoidance of excessive alcohol, meat and caloric consumption, increasing physical activity and frequent consumption of vegetables and fruits are prudent lifestyle modifications for the prevention of EC as well as other diseases. Key Message: The etiology of EC includes tobacco smoking, alcohol drinking, low levels of intake of fruits and vegetables as well as gastroesophageal reflux and susceptibility genes. Practical Implications: A healthy lifestyle including smoking cessation, increasing physical activity, consumption of vegetables as well as reduction of alcohol intake and caloric consumption are major approaches to the prevention of EC.

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Supportive evidence for FOXP1,BARX1, and FOXF1 as genetic risk loci for the development of esophageal adenocarcinoma

Cited by 25 publications

References 11 publications

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

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

Genetic polymorphisms are associated with the risk of gastric and colorectal cancers in a Han Chinese population

Etiology and Prevention of Esophageal Cancer

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