Dynamic clonal equilibrium and predetermined cancer risk in Barrett's oesophagus.
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ABSTRACT:
SUBMITTER: Martinez P
PROVIDER: S-EPMC4992167 | biostudies-literature | 2016 Aug
REPOSITORIES: biostudies-literature
Publications
Dynamic clonal equilibrium and predetermined cancer risk in Barrett's oesophagus.
Martinez Pierre P Timmer Margriet R MR Lau Chiu T CT Calpe Silvia S Sancho-Serra Maria Del Carmen Mdel C Straub Danielle D Baker Ann-Marie AM Meijer Sybren L SL Kate Fiebo J W Ten FJ Mallant-Hent Rosalie C RC Naber Anton H J AH van Oijen Arnoud H A M AH Baak Lubbertus C LC Scholten Pieter P Böhmer Clarisse J M CJ Fockens Paul P Bergman Jacques J G H M JJ Maley Carlo C CC Graham Trevor A TA Krishnadath Kausilia K KK
Nature communications 20160819
Surveillance of Barrett's oesophagus allows us to study the evolutionary dynamics of a human neoplasm over time. Here we use multicolour fluorescence in situ hybridization on brush cytology specimens, from two time points with a median interval of 37 months in 195 non-dysplastic Barrett's patients, and a third time point in a subset of 90 patients at a median interval of 36 months, to study clonal evolution at single-cell resolution. Baseline genetic diversity predicts progression and remains in ...[more]
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Project description:BACKGROUND:Barrett's oesophagus (BO) is a premalignant condition associated with the development of oesophageal adenocarcinoma (OAC). Globally, the incidence of OAC is rising. Furthermore, the prognosis regarding the morbidity and mortality of OAC is bleak, with an estimated 5-year survival of 10-15%. Hence, detection of the premalignant phase is paramount. Endoscopy and biopsy sampling is the mainstay of diagnosis. Patients may present with symptoms of gastro-oesophageal reflux disease (GORD) or be completely asymptomatic. Therefore, symptomatology alone is a poor indicator of this condition. SUMMARY:This review highlights the current risk factors associated with the development of BO. KEY MESSAGE:Primary risk factors for BO include male gender, increased age, a family history of the disease, long-standing GORD, smoking, obesity (specifically determined by the waist-to-hip ratio as opposed to BMI), and Caucasian race. Alcohol consumption and Helicobacter pylori are not associated with the condition. PRACTICAL IMPLICATIONS:By ensuring an appropriate understanding of the risk factors, clinicians can discern at-risk patients for endoscopic diagnosis and surveillance.
| S-EPMC5121541 | biostudies-literature
Project description:OBJECTIVE:The risk of developing adenocarcinoma in non-dysplastic Barrett's oesophagus is low and difficult to predict. Accurate tools for risk stratification are needed to increase the efficiency of surveillance. We aimed to develop a prediction model for progression using clinical variables and genetic markers. METHODS:In a prospective cohort of patients with non-dysplastic Barrett's oesophagus, we evaluated six molecular markers: p16, p53, Her-2/neu, 20q, MYC and aneusomy by DNA fluorescence in situ hybridisation on brush cytology specimens. Primary study outcomes were the development of high-grade dysplasia or oesophageal adenocarcinoma. The most predictive clinical variables and markers were determined using Cox proportional-hazards models, receiver operating characteristic curves and a leave-one-out analysis. RESULTS:A total of 428 patients participated (345 men; median age 60?years) with a cumulative follow-up of 2019 patient-years (median 45?months per patient). Of these patients, 22 progressed; nine developed high-grade dysplasia and 13 oesophageal adenocarcinoma. The clinical variables, age and circumferential Barrett's length, and the markers, p16 loss, MYC gain and aneusomy, were significantly associated with progression on univariate analysis. We defined an 'Abnormal Marker Count' that counted abnormalities in p16, MYC and aneusomy, which significantly improved risk prediction beyond using just age and Barrett's length. In multivariate analysis, these three factors identified a high-risk group with an 8.7-fold (95% CI 2.6 to 29.8) increased HR when compared with the low-risk group, with an area under the curve of 0.76 (95% CI 0.66 to 0.86). CONCLUSIONS:A prediction model based on age, Barrett's length and the markers p16, MYC and aneusomy determines progression risk in non-dysplastic Barrett's oesophagus.
| S-EPMC4988941 | biostudies-literature
Project description:Oesophageal adenocarcinoma is rapidly increasing in Western countries. This tumour frequently presents late in its course with metastatic disease and has a very poor prognosis. Barrett's oesophagus is an acquired condition whereby the native squamous mucosa of the lower oesophagus is replaced by columnar epithelium following prolonged gastro-oesophageal reflux and is the recognised precursor lesion for oesophageal adenocarcinoma. There are multiple national and society guidelines regarding screening, surveillance and management of Barrett's oesophagus, however all are limited regarding a clear evidence base for a well-demonstrated benefit and cost-effectiveness of surveillance, and robust risk stratification for patients to best use resources. Currently the accepted risk factors upon which surveillance intervals and interventions are based are Barrett's segment length and histological interpretation of the systematic biopsies. Further patient risk factors including other demographic features, smoking, gender, obesity, ethnicity, patient age, biomarkers and endoscopic adjuncts remain under consideration and are discussed in full. Recent evidence has been published to support earlier endoscopic intervention by means of ablation of the metaplastic Barrett's segment when the earliest signs of dysplasia are detected. Further work should concentrate on establishing better risk stratification and primary and secondary preventative strategies to reduce the risk of adenocarcinoma of the oesophagus.
| S-EPMC5537175 | biostudies-other
Project description:Barrett's oesophagus (BE) is the precursor lesion to adenocarcinoma of the oesophagus. Understanding of the molecular alterations in this multistage process may contribute to improved diagnosis and treatment. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that modulates cell adhesion and growth. Alterations in SPARC expression have been observed in a variety of solid tumours. The aim of this study was to assess the prevalence and timing of SPARC mRNA expression in Barrett's multistage disease and to investigate the impact of SPARC alterations on the development and progression of this disease. SPARC mRNA expression was measured using a quantitative real-time RT-PCR method in 108 specimens from 19 patients with BE without carcinoma, 20 patients with Barrett's-associated adenocarcinoma (EA), and a control group (CG) of 10 patients without evidence of gastro-oesophageal reflux disease. The median SPARC mRNA expression was significantly upregulated in BE tissues compared to paired normal oesophagus (NE) tissues for the BE group (P=0.004) and for the EA group (P<0.001). The SPARC mRNA expression was significantly higher in adenocarcinoma of the oesophagus compared to matching NE tissue and compared to Barrett's tissues in the EA group (P<0.001). Furthermore, SPARC expression values were significantly different between metaplastic and dysplastic Barrett's tissues (P=0.014). In histologically normal squamous oesophagus tissues obtained from carcinoma patients (EA group), the SPARC mRNA expression was significantly higher compared to NE mucosa from the BE group and the CG group (P=0.03). These findings suggest that the upregulation of SPARC mRNA expression is an early event in the development and progression of BE and EA, and that high SPARC expression may be a clinically useful biomarker for the detection of occult adenocarcinoma, and that a widespread 'field effect' is present in the NE of patients with oesophageal adenocarcinoma.
| S-EPMC2394336 | biostudies-literature
Project description:Body mass index is associated with the risk of Barrett's oesophagus (BO). It is uncertain whether this is related to total body fat or other factors that correlate with body mass index. We aimed to quantify the association between total body fat (measured by bioelectrical impedance) and risk of BO and examine if this association was modified by gastro-oesophageal reflux (GOR) and abdominal obesity.In 2007-2009, we surveyed 235 cases (69% Males, Mean age 62.1 years) and 244 age and sex matched population controls from a population based case-control study of BO. We conducted structured interviews, standard anthropometry and bioimpedance analysis of total body fat. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using multivariable logistic regression analysis.There was a significantly increased risk of BO among those in the highest tertile of total body fat weight (OR 2.01; 95%CI 1.26-3.21) and total body fat percentage (OR 1.86; 95%CI 1.10-3.15). These risks were largely attenuated after adjustment for GOR and waist circumference. There was a significantly increased risk of BO among those in the highest tertile of waist circumference (OR 2.21; 95%CI 1.39-3.51) and this was minimally attenuated after adjustment for total body fat and moderately attenuated after adjustment for GOR.Total body fat is associated with an increased risk of BO but this appears to be mediated via both abdominal obesity and GOR. These findings provide evidence that abdominal obesity is more important than total body fat in the development of BO.
| S-EPMC4180020 | biostudies-literature
Project description:OBJECTIVE:Barrett's oesophagus (BE) increases the risk of oesophageal adenocarcinoma by 10-55 times that of the general population, but no community-based cancer-specific incidence and cause-specific mortality risk estimates exist for large cohorts in the USA. DESIGN:Within Kaiser Permanente Northern California (KPNC), we identified patients with BE diagnosed during 1995-2012. KPNC cancer registry and mortality files were used to estimate standardised incidence ratios (SIR), standardised mortality ratios (SMR) and excess absolute risks. RESULTS:There were 8929 patients with BE providing 50?147 person-years of follow-up. Compared with the greater KPNC population, patients with BE had increased risks of any cancer (SIR=1.40, 95% CI 1.31 to 1.49), which slightly decreased after excluding oesophageal cancer. Oesophageal adenocarcinoma risk was increased 24 times, which translated into an excess absolute risk of 24 cases per 10?000 person-years. Although oesophageal adenocarcinoma risk decreased with time since BE diagnosis, oesophageal cancer mortality did not, indicating that the true risk is stable and persistent with time. Relative risks of cardia and stomach cancers were increased, but excess absolute risks were modest. Risks of colorectal, lung and prostate cancers were unaltered. All-cause mortality was slightly increased after excluding oesophageal cancer (SMR=1.24, 95% CI 1.18 to 1.31), but time-stratified analyses indicated that this was likely attributable to diagnostic bias. Cause-specific SMRs were elevated for ischaemic heart disease (SMR=1.39, 95% CI 1.18 to 1.63), respiratory system diseases (SMR=1.51, 95% CI 1.29 to 1.75) and digestive system diseases (SMR=2.20 95% CI 1.75 to 2.75). CONCLUSIONS:Patients with BE had a persistent excess risk of oesophageal adenocarcinoma over time, although their absolute excess risks for this cancer, any cancer and overall mortality were modest.
| S-EPMC5827961 | biostudies-literature
Project description:Concern exists that patients born with oesophageal atresia (OA) may be at high risk for Barrett's oesophagus (BO), a known malignant precursor to the development of oesophageal adenocarcinoma. Screening endoscopy has a role in early BO identification but is not universal in this population. This study aimed to determine prevalence of BO after OA repair surgery, to quantify the magnitude of this association and inform the need for screening and surveillance. A systematic review, undertaken according to PRISMA guidelines, was preregistered on PROSPERO (CRD42017081001). PubMed and EMBASE were interrogated using a standardized search strategy on 31 July 2020. Included papers, published in English, reported either: one or more patients with either BO (gastric/intestinal metaplasia) or oesophageal cancer in patients born with OA; or long-term (greater than 2 years) follow-up after OA surgery with or without endoscopic screening or surveillance. Some 134 studies were identified, including 19 case reports or series and 115 single- or multi-centre cohort studies. There were 13 cases of oesophageal cancer (9 squamous cell carcinoma, 4 adenocarcinoma) with a mean age at diagnosis of 40.5 (range 20-47) years. From 6282 patients under long-term follow-up, 317 patients with BO were reported. Overall prevalence of BO was 5.0 (95 per cent c.i. 4.5 to 5.6) per cent, with a mean age at detection of 13.8 years (range 8 months to 56 years). Prevalence of BO in series reporting endoscopic screening or surveillance was 12.8 (95 per cent c.i. 11.3 to 14.5) per cent. Despite a limited number of cancers, the prevalence of BO in patients born with OA is relatively high. While limited by the quality of available evidence, this review suggests endoscopic screening and surveillance may be warranted, but uncertainties remain over the design and effectiveness of any putative programme.
| S-EPMC8405903 | 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:Barrett's oesophagus (BO) is a common condition, predisposing strongly to the development of oesophageal adenocarcinoma (OAC). Consequently, there has been considerable effort to determine the processes involved in the development of BO metaplasia, and ultimately develop markers of patients at risk. Whilst a number of robust acquired risk factors have been identified, a genetic component to these and the apparent increased susceptibility of certain individuals has long been suspected. This has been evidenced in part by linkage studies, but subsequently two recent genome-wide association studies (GWAS) have suggested mechanisms underlying the heritability of BO, as well as providing the first direct evidence at modern levels of statistical significance. This review discusses BO heritability, in addition to that of individual variants and genes reported to be associated with BO to date. Through this, we identify a number of plausible associations, although often tempered by issues of methodology, and discuss the priorities and need for future research.
| S-EPMC4971784 | biostudies-literature
Project description:Purpose of reviewThe targeted approach adopted for Barrett's oesophagus (BO) screening is sub-optimal considering the large proportion of BO cases that are currently missed. We reviewed the literature highlighting recent technological advancements in efforts to counteract this challenge. We also provided insights into strategies that can improve the outcomes from current BO screening practises.Recent findingsThe standard method for BO detection, endoscopy, is invasive and expensive and therefore inappropriate for mass screening. On the other hand, endoscopy is more cost-effective for screening a high-risk population. A consensus has however not been reached on who should be screened. Risk prediction algorithms have been tested as an enrichment pre-screening tool reporting modest AUC's but require more prospective evaluation studies. Less invasive endoscopy methods like trans-nasal endoscopy, oesophageal capsule endsocopy and non-endoscopic cell collection devices like the Cytosponge coupled with biomarker analysis have shown promise in BO detection with randomised clinical trial evidence.SummaryA three-tier precision cancer programme whereby risk prediction algorithms and non-endoscopic minimally invasive cell collection devices are used to triage test a wider pool of individuals may improve the detection rate of current screening practises with minimal cost implications.
| S-EPMC7962426 | biostudies-literature