Genome-wide association studies in oesophageal adenocarcinoma and Barrett's oesophagus: a large-scale meta-analysis.
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ABSTRACT:
SUBMITTER: Gharahkhani P
PROVIDER: S-EPMC5052458 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveTo identify and characterise DNA methylation subtypes in oesophageal adenocarcinoma (EAC) and its precursor Barrett's oesophagus (BE).DesignWe performed genome-wide DNA methylation profiling on samples of non-dysplastic BE from cancer-free patients (n=59), EAC (n=23), normal squamous oesophagus (n=33) and normal fundus (n=9), and identified methylation subtypes using a recursively partitioned mixture model. We assessed genomic alterations for 9 BE and 22 EAC samples with massively parallel sequencing of 243 EAC-associated genes, and we conducted integrative analyses with transcriptome data to identify epigenetically repressed genes. We also carried out in vitro experiments treating EAC cell lines with 5-Aza-2'-Deoxycytidine (5-Aza-dC), short hairpin RNA knockdown and anticancer therapies.ResultsWe identified and validated four methylation subtypes of EAC and BE. The high methylator subtype (HM) of EAC had the greatest number of activating events in ERBB2 (p<0.05, Student's t-test) and the highest global mutation load (p<0.05, Fisher's exact test). PTPN13 was silenced by aberrant methylation in the HM subtype preferentially and in 57% of EACs overall. In EAC cell lines, 5-Aza-dC treatment restored PTPN13 expression and significantly decreased its promoter methylation in HM cell lines (p<0.05, Welch's t-test). Inhibition of PTPN13 expression in the SK-GT-4 EAC cell line promoted proliferation, colony formation and migration, and increased phosphorylation in ERBB2/EGFR/Src kinase pathways. Finally, EAC cell lines showed subtype-specific responses to topotecan, SN-38 and palbociclib treatment.ConclusionsWe identified and characterised methylator subtypes in BE and EAC. We further demonstrated the biological and clinical relevance of EAC methylator subtypes, which may ultimately help guide clinical management of patients with EAC.
| S-EPMC6565505 | biostudies-literature
Project description:The public health importance of Barrett's oesophagus lies in its association with oesophageal adenocarcinoma. The incidence of oesophageal adenocarcinoma has risen at an alarming rate over the past four decades in many regions of the Western world, and there are indications that the incidence of this disease is on the rise in Asian populations in which it has been rare. Much has been learned of host and environmental risk factors that affect the incidence of oesophageal adenocarcinoma, and data indicate that patients with Barrett's oesophagus rarely develop oesophageal adenocarcinoma. Given that 95% of oesophageal adenocarcinomas arise in individuals without a prior diagnosis of Barrett's oesophagus, what strategies can be used to reduce late diagnosis of oesophageal adenocarcinoma?
| S-EPMC2879265 | biostudies-literature
Project description:BackgroundA systematic review suggests that 25% of oesophageal adenocarcinomas (OAC) are 'missed' at index endoscopy for Barrett's oesophagus (BO); however, this included few population-based studies and may be an overestimate.ObjectiveThe objective of this article is to quantify the 'missed' rates of high-grade dysplasia (HGD) and OAC at index BO endoscopy.MethodsPatients from the Northern Ireland BO register diagnosed between 1993 and 2010 (n?=?13,159) were linked to the Northern Ireland Cancer Registry to identify patients who developed OAC or HGD. Logistic regression analysis compared characteristics of 'missed' vs 'incident' HGD/OAC, defined as diagnoses within 3-12 months vs >1 year after incident BO, respectively.ResultsA total of 267 patients were diagnosed with HGD/OAC ?3 months after BO diagnosis, of whom 34 (12.7%) were potentially 'missed'. The proportion of 'missed' HGD/OAC was 25% among BO patients with low-grade dysplasia (LGD) and 9% among non-dysplastic BO patients. Older age and BO-LGD carried a higher risk of 'missed' HGD/OAC. Non-dysplastic BO patients were more often diagnosed with a 'missed' OAC (rather than HGD; 89%), compared with BO-LGD patients (40%).ConclusionsApproximately one in 10 HGD/OAC cases are 'missed' at incident BO diagnosis, which is significant but lower than previous reports. However, 'missed' HGD/OAC cases represent only 0.26% of all BO patients.
| S-EPMC5987274 | biostudies-literature
Project description:BACKGROUND: Biomarkers are needed to improve current diagnosis and surveillance strategies for patients with Barrett's oesophagus (BO) and oesophageal adenocarcinoma (OAC). Macrophage inhibitory cytokine 1/growth differentiation factor 15 (MIC-1/GDF15) tissue and plasma levels have been shown to predict disease progression in other cancer types and was therefore evaluated in BO/OAC. METHODS: One hundred thirty-eight patients were studied: 45 normal oesophagus (NE), 37 BO, 16 BO with low-grade dysplasia (LGD) and 40 OAC. RESULTS: Median tissue expression of MIC-1/GDF15 mRNA was ⩾25-fold higher in BO and LGD compared to NE (P<0.001); two-fold higher in OAC vs BO (P=0.039); and 47-fold higher in OAC vs NE (P<0.001). Relative MIC-1/GDF15 tissue expression >720 discriminated between the presence of either OAC or LGD vs NE with 94% sensitivity and 71% specificity (ROC AUC 0.86, 95% CI 0.73-0.96; P<0.001). Macrophage inhibitory cytokine 1/growth differentiation factor 15 plasma values were also elevated in patients with OAC vs NE (P<0.001) or BO (P=0.015).High MIC-1/GDF15 plasma levels (⩾1140 pg ml(-1)) were an independent predictor of poor survival for patients with OAC (HR 3.87, 95% CI 1.01-14.75; P=0.047). CONCLUSIONS: Plasma and tissue levels of MIC-1/GDF15 are significantly elevated in patients with BO, LGD and OAC. Plasma MIC-1/GDF15 may have value in diagnosis and monitoring of Barrett's disease.
| S-EPMC4402450 | biostudies-other
Project description:BackgroundThe proportions of patients with oesophageal adenocarcinoma (OAC) diagnosed by Barrett's oesophagus surveillance or with pre-existing Barrett's oesophagus are unclear.AimTo estimate the prevalence of prior and concurrent Barrett's oesophagus diagnosis among patients with OAC or oesophagogastric junction adenocarcinomas (OGJAC).MethodsWe searched PubMed and Embase to identify studies published 1966-1/8/2020 that examined the prevalence of prior (≥6 months) or concurrent Barrett's diagnosis (at cancer diagnosis) among OAC and OGJAC patients. Random effects models estimated overall and stratified pooled prevalence rates.ResultsA total of 69 studies, including 33 002 OAC patients (53 studies) and 2712 patients with OGJAC (28 studies) were included. The pooled prevalence of prior Barrett's oesophagus diagnosis in OAC was 11.8% (95% confidence interval [CI] 8.4%-15.6%). The prevalence of prior Barrett's oesophagus diagnosis was higher in single-centre resection studies (16.0%, 95% CI 8.7%-24.9%) than population-based cancer registry studies (8.4%, 95% CI 5.5%-11.9%). The prevalence of concurrent Barrett's oesophagus in OAC was 56.6% (95% CI 48.5%-64.6%). Studies with 100% early stage OAC had higher prevalence of concurrent Barrett's oesophagus (91.3%, 95% CI 82.4%-97.6%) than studies with <50% early OAC (39.7%, 95% CI 33.7%-45.9%). In OGJAC, the prevalence of prior and concurrent Barrett's oesophagus was 23.2% (95% CI 7.5%-44.0%) and 26.3% (95% CI 17.8%-35.7%), respectively.ConclusionsMost patients with OAC have Barrett's oesophagus. Our meta-analysis found ~12% of OAC patients had prior Barrett's diagnosis, but concurrent Barrett's oesophagus was found in ~57% at the time of OAC diagnosis. This represents a considerable missed opportunity for Barrett's oesophagus screening.
| S-EPMC7293564 | biostudies-literature
Project description:BACKGROUND:Based on reported familial patterns, inheritance of a predisposition of developing Barrett's oesesophagus (BO) and oesophageal adenocarcinoma (OAC) likely follows an autosomal dominant model of most inherited cancer syndromes. oesophagus (BO) and oesophageal adenocarcinoma (OAC) likely follows an autosomal dominant model of most inherited cancer syndromes. AIMS:We analysed the phenotypic features of 70 familial BO/OAC families accrued for the purpose of initiating a linkage study to search for genes that contribute to susceptibility for BO/OAC. METHODS:Families with young or familial BO/OAC were recruited from participating institutions and self-referral from advertisement. RESULTS:A total of 70 families (173 affected and 784 unaffected individuals) were recruited into this study. Mean ages of diagnosis of BO and OAC among males were 50.6 and 57.4 years, respectively; among females, 52.1 and 63.5 years, respectively. The standardised incidence ratio (SIR) of cancers other than OAC or oesophagogastric junctional adenocarcinoma (OGJAC), among probands was 0.71. Seventy one percent of the pedigrees have "typical" structures with less than three affected individuals. Power calculations under realistic model assumptions suggest that if genetic heterogeneity is absent or limited, then DNA collection from members of these pedigrees could enable the identification of a novel candidate susceptibility gene for BO/OAC in a genome scan. CONCLUSIONS:This is the largest series of families with BO/OAC yet reported, features of which are consistent with inherited germline predisposition. Further, the SIR of cancers other than OAC/OGJAC was 0.71 among 70 probands, indicating these individuals were not more likely to develop non-OAC cancers.
| S-EPMC1735581 | biostudies-literature
Project description:OBJECTIVE:Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA. DESIGN:We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-?B. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. RESULTS:We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10-5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk. CONCLUSIONS:This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility.
| S-EPMC5296402 | biostudies-literature
Project description:Circulating microRNAs (miRNAs) are promising biomarkers for the early detection of cancers. This study aimed to address potential circulating miRNAs to monitor the progression from Barrett's oesophagus (BO) to oesophageal adenocarcinoma (OAC).We comprehensively analysed tissue and serum miRNA expression profiles of BO mice model (L2-interleukin-1? (IL-1?) mice) using microarray analysis. To validate the data from mice, a published dataset of human plasma miRNAs, consisting of eight patients with OAC, eight with BO and six healthy controls, was used (GSE51410).We identified 20 upregulated miRNAs and 44 downregulated miRNAs both in tissues and in sera of 46-week-old mice compared with 28-week-old mice. Two of the 20 miRNAs (miR-128-3?p and miR-328-3?p) were upregulated, and five of the 44 miRNAs (miR-143-3?p, miR-144-3?p, miR-15a-5p, miR-1-3?p and miR-133b) were downregulated in plasma of patients with OAC compared with plasma of patients with BO. Receiver operating characteristic curve analysis revealed that a prediction index calculated by the above-mentioned seven miRNAs could discriminate between patients with OAC and those without OAC with the area under the curve of 0.91, sensitivity of 1 and specificity of 0.75.Levels of the seven circulating miRNAs may represent the tissue miRNA levels and could be promising non-invasive biomarkers to evaluate the carcinogenic process of BO.
| S-EPMC5689485 | biostudies-literature
Project description:BackgroundCurrent guidelines recommend different screening approaches for individuals with a family history of Barrett's oesophagus (BO) or oesophageal adenocarcinoma (OAC), varying from no screening to screening all individuals with a positive family history.AimsTo determine evidence-based risk estimates for individuals with a family history of BO or OAC METHODS: We systematically searched Pubmed, Embase and Cochrane Library until October 2020 to identify all studies that reported on the association between family history and the risk of BO and OAC. Pooled summary estimates of adjusted relative risks and prevalence of familial BO/OAC with 95% confidence intervals (CIs) were calculated using a random effects model.ResultsFourteen studies comprising 16 189 BO/OAC patients were analysed. Familial clustering was seen in 8.84% (95% CI: 5.54-13.82) and 4.37% (95% CI: 2.15-8.69) of patients with BO and OAC, respectively (nine studies). Screening first-degree relatives of BO patients had a diagnostic yield between 12% and 44% for BO (four studies). However, the yield for high-grade dysplasia and OAC was low (<2%). Individuals with a positive family history had a higher risk of having BO (aRR 3.26; 95% CI 1.43-7.40; I2 = 46%; three studies) and OAC (aRR 2.19; 95% CI 1.14-4.21; I2 = 48%; five studies) compared to individuals without a family history.ConclusionsA verified family history of BO or OAC is a strong risk factor for both BO and OAC. A positive family history could be a clinically meaningful way to identify high-risk individuals who may benefit from early detection strategies.
| S-EPMC9292032 | biostudies-literature
Project description:Background and aimsAcid-suppressive medications, particularly proton pump inhibitors (PPIs), may decrease the risk of oesophageal adenocarcinoma (OAC) in patients with Barrett's oesophagus (BO). We performed a systematic review with meta-analysis of studies evaluating the association between acid-suppressive medications (PPIs and histamine receptor antagonists (H2RAs)) and risk of OAC or high-grade dysplasia (BO-HGD) in patients with BO.MethodsWe performed a systematic search of multiple electronic databases and conference proceedings up to June 2013 to identify studies reporting the association between use of acid-suppressive medications and risk of OAC and/or BO-HGD in patients with BO. Summary ORs with 95% CIs were estimated.ResultsWe identified seven observational studies (2813 patients with BO, 317 cases of OAC or BO-HGD, 84.4% PPI users). On meta-analysis, PPI use was associated with a 71% reduction in risk of OAC and/or BO-HGD in patients with BO (adjusted OR 0.29; 95% CI 0.12 to 0.79). There was a trend towards a dose-response relationship with PPI use for >2-3 years protective against OAC or BO-HGD (three studies; PPI use >2-3 years vs <2-3 years: OR 0.45 (95% CI 0.19 to 1.06) vs 1.09 (0.47 to 2.56)). Considerable heterogeneity was observed. Two studies reported the association between H2RA use and risk of OAC and/or BO-HGD (1352 patients with BO, 156 cases of OAC, 25.4% on H2RAs), and both studies did not show a significant effect.ConclusionsBased on meta-analysis of observational studies, the use of PPIs is associated with a decreased risk of OAC and/or BO-HGD in patients with BO. None of the studies showed an increased risk of OAC. PPI use should be considered in BO, and chemopreventive trials of PPIs in patients with BO are warranted.
| S-EPMC4199831 | biostudies-literature