Wendy Brock

Familial aggregation of Barrett’s oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults

Background: Although familial clusters of Barrett’s oesophagus and oesophageal adenocarcinoma have been reported, a familial predisposition to these diseases has not been systematically investigated. Aims: To determine whether Barrett’s oesophagus and oesophageal (or oesophagogastric junctional) adenocarcinoma aggregate in families. Patients and methods: A structured questionnaire eliciting details on reflux symptoms, exposure history, and family history was given to Caucasian case (n=58) subjects with Barrett’s oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma, and to Caucasian control (n=106) subjects with symptomatic gastro-oesophageal reflux disease without Barrett’s oesophagus. Reported diagnoses of family members were confirmed by review of medical records. Results: The presence of a positive family history (that is, first or second degree relative with Barrett’s oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma) was significantly higher among case subjects compared with controls (24% v 5%; p<0.005). Case subjects were more likely to be older (p<0.001) and male (74% v 43% male; p<0.0005) compared with control subjects. In a multivariate logistic regression analysis, family history was independently associated with the presence of Barrett’s oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma (odds ratio 12.23, 95% confidence interval 3.34–44.76) after adjusting for age, sex, and the presence of obesity 10 or more years prior to study enrolment. Conclusions: Individuals with Barrett’s oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma are more likely to have a positive family history of Barrett’s oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma than individuals without Barrett’s oesophagus, oesophageal adenocarcinoma, or oesophagogastric junctional adenocarcinoma. A positive family history should be considered when making decisions about screening endoscopy in patients with symptoms of gastro-oesophageal reflux.

Identification of Barrett's Esophagus in Relatives by Endoscopic Screening

AIM:Familial aggregation of Barretts esophagus and its associated cancers has been termed familial Barretts esophagus (FBE). The aim of the study was to determine whether endoscopic screening would identify Barretts esophagus (BE) in relatives of probands with BE or esophageal adenocarcinoma (EAC).METHODS:All living first-degree relatives of patients with long segment BE or EAC presenting to the endoscopy suite of two academic hospitals were sent validated questionnaires inquiring about gastroesophageal reflux symptoms and prior endoscopic evaluation. First-degree relatives of affected probands or affected relatives who reported no prior upper endoscopy were offered screening unsedated esophagoscopy. Relatives with chronic gastroesophageal reflux symptoms were also offered an alternative of conventional sedated upper endoscopy. The yield of screening endoscopy was measured. Screening endoscopy findings were then compared between family members of known FBE patients and those with “isolated” disease.RESULTS:One hundred and ninety-eight relatives from 69 families, 23 known FBE probands and 46 probands with apparently “isolated” disease, were enrolled. Forty relatives (29 FBE relatives and 11 relatives of probands with “isolated” disease) reported prior upper endoscopy. Screening upper endoscopies performed on 62 (25 FBE and 37 “isolated” disease relatives) of the remaining 158 relatives identified Barretts epithelium in 13 (21%). Compared to probands with apparently “isolated” disease, Barretts epithelium (EAC, BE, or SSBE) was identified significantly more often in siblings and offspring of FBE probands, p≤ 0.05. Endoscopic screening of relatives of FBE probands identified a multigeneration multiplex FBE pedigree consistent with an autosomally dominant inherited trait. Endoscopic screening of relatives of probands with reported “isolated” diseased did not identify any new FBE pedigrees.CONCLUSIONS:Endoscopy identified EAC, long-segment BE, and short-segment BE in a substantial proportion of first-degree relatives of affected members of FBE families. A familial susceptibility to develop Barretts epithelium appears to be present in a subset of patients with BE and EAC.

Demographic and phenotypic features of 70 families segregating Barrett’s oesophagus and oesophageal adenocarcinoma

Background: Barrett’s oesophagus (BO) also termed metaplastic columnar lined oesophageal epithelium, is believed to result from a continual reparative response to chronic reflux of gastric contents. Although traditionally considered to be an acquired disorder, with several epidemiological risk factors involved, it is now recognised that there is a genetic component, and that this is likely to be autosomal dominant. Clustering of BO and of oesophageal adenocarcinoma (OAC) or oesophagogastric junctional adenocarcinoma (OGJAC) has been shown in a number of studies. Methods: We investigated a large series of BO/OAC families to find evidence that a subset of BO/OAC is the result of a hereditary predisposition, and explored the potential of performing a linkage study with the families identified to date. Results: Of 957 individuals in 70 families, 173 had a reported diagnosis of BO or OAC/OGJAC: 101 had BO only, 52 had OAC/OGJAC, and 20 had both BO and OAC/OGJAC. There were 133 affected males and 40 affected females, a male:female ratio of 3.3:1. In addition, 124 participants (12.9%) had a reported diagnosis of cancer other than OAC. Of these, 15 did (affected) and 109 did not (unaffected) have a diagnosis of BO or OAC. A cancer other than OAC was found in 13.9% of unaffected and 8.7% of affected individuals. Conclusion: It is widely accepted that the majority of BO and OAC are sporadic, although familial clustering of BO and OAC has been recognised for at least three decades. Environment and lifestyle undoubtedly play a role in development of BO and OAC, and may affect the penetrance of the putative inherited factor. Although our 70 BO probands were not more likely to develop non-OAC/OGJAC cancers than normal, over a third had developed either OAC or OGJAC, and might have gone on to develop others. We intend to continue recruitment and initiate formal linkage studies to identify the causative gene(s).

Assessment of Familiality, Obesity, and Other Risk Factors for Early Age of Cancer Diagnosis in Adenocarcinomas of the Esophagus and Gastroesophageal Junction

OBJECTIVES:Adenocarcinomas of the esophagus and adenocarcinomas of the gastroesophageal junction are postulated to be complex genetic diseases. Combined influences of environmental factors and genetic susceptibility likely influence the age at which these cancers develop. The aim of this study was to determine whether familiality and other recognized risk factors are associated with the development of these cancers at an earlier age.METHODS:A structured validated questionnaire was utilized to collect self-reported data on gastro-esophageal reflux symptoms, risk factors for Barretts esophagus (BE) and family history, including age of cancer diagnosis in affected relatives from probands with BE, adenocarcinoma of the esophagus, or adenocarcinoma of the gastroesophageal junction, at five tertiary care academic hospitals. Medical records of all relatives reported to be affected were requested from hospitals providing this cancer care to confirm family histories. Familiality of BE/cancer, obesity (defined as body mass index >30), gastroesophageal reflux symptoms, and other risk factors were assessed for association with a young age of cancer diagnosis.RESULTS:A total of 356, 216 non-familial and 140 familial, cancers were studied. The study population consisted of 292 (82%) men and 64 (18%) women. Mean age of cancer diagnosis was no different in a comparison of familial and non-familial cancers, 62.6 vs. 61.9 years, P=0.70. There were also no significant differences in symptoms of gastroesophageal reflux, body mass index, race, gender, and smoking history between familial and non-familial cancers. Mean age of cancer diagnosis was significantly younger in those who were obese 1 year before diagnosis as compared to those who were non-obese, mean age 58.99 vs. 63.6 years, P=0.008. Multivariable modeling of age at cancer diagnosis showed that obesity 1 year before diagnosis was associated with a younger age of cancer diagnosis (P=0.005) after adjustment for heartburn and regurgitation duration.CONCLUSIONS:Obesity is associated with the development of esophageal and gastroesophageal junctional adenocarcinomas at an earlier age. Familial cancers arise at the same age as non-familial cancers and have a similar risk factor profile.

A Segregation Analysis of Barrett's Esophagus and Associated Adenocarcinomas

Familial aggregation of esophageal adenocarcinomas, esophagogastric junction adenocarcinomas, and their precursor Barretts esophagus (BE) has been termed familial BE (FBE). Numerous studies documenting increased familial risk for these diseases raise the hypothesis that there may be an inherited susceptibility to the development of BE and its associated cancers. In this study, using segregation analysis for a binary trait as implemented in S.A.G.E. 6.0.1, we analyzed data on 881 singly ascertained pedigrees to determine whether FBE is caused by a common environmental or genetic agent and, if genetic, to identify the mode of inheritance of FBE. The inheritance models were compared by likelihood ratio tests and Akaikes A Information Criterion. Results indicated that random environmental and/or multifactorial components were insufficient to fully explain the familial nature of FBE, but rather, there is segregation of a major type transmitted from one generation to the next (P < 10−10). An incompletely dominant inheritance model together with a polygenic component fits the data best. For this dominant model, the estimated penetrance of the dominant allele is 0.1005 [95% confidence interval (95% CI), 0.0587-0.1667] and the sporadic rate is 0.0012 (95% CI, 0.0004-0.0042), corresponding to a relative risk of 82.53 (95% CI, 28.70-237.35) or odds ratio of 91.63 (95% CI, 32.01-262.29). This segregation analysis provides epidemiologic evidence in support of one or more rare autosomally inherited dominant susceptibility allele(s) in FBE families and, hence, motivates linkage analyses. Cancer Epidemiol Biomarkers Prev; 19(3); 666–74

Identifying DNA methylation biomarkers for non-endoscopic detection of Barrett’s esophagus

Combining DNA methylation markers with a swallowable device for sampling the distal esophagus effectively detects Barrett’s neoplasias. A test that goes down easy Barrett’s esophagus is a premalignant condition of the distal esophagus that increases the risk of esophageal cancer. Unfortunately, screening for Barrett’s esophagus currently requires endoscopy, an invasive and expensive procedure, and thus, it is not routinely performed. Moinova et al. have now demonstrated a simplified approach to screening by identifying a pair of DNA methylation markers that correlate with the presence of Barrett’s esophagus. The authors also invented a swallowable balloon-based device that can capture DNA samples for methylation analysis and found that it is well tolerated in patients and provides >90% sensitivity and specificity compared to endoscopy, suggesting its potential as a screening method. We report a biomarker-based non-endoscopic method for detecting Barrett’s esophagus (BE) based on detecting methylated DNAs retrieved via a swallowable balloon-based esophageal sampling device. BE is the precursor of, and a major recognized risk factor for, developing esophageal adenocarcinoma. Endoscopy, the current standard for BE detection, is not cost-effective for population screening. We performed genome-wide screening to ascertain regions targeted for recurrent aberrant cytosine methylation in BE, identifying high-frequency methylation within the CCNA1 locus. We tested CCNA1 DNA methylation as a BE biomarker in cytology brushings of the distal esophagus from 173 individuals with or without BE. CCNA1 DNA methylation demonstrated an area under the curve of 0.95 for discriminating BE-related metaplasia and neoplasia cases versus normal individuals, performing identically to methylation of VIM DNA, an established BE biomarker. When combined, the resulting two biomarker panel was 95% sensitive and 91% specific. These results were replicated in an independent validation cohort of 149 individuals who were assayed using the same cutoff values for test positivity established in the training population. To progress toward non-endoscopic esophageal screening, we engineered a well-tolerated, swallowable, encapsulated balloon device able to selectively sample the distal esophagus within 5 min. In balloon samples from 86 individuals, tests of CCNA1 plus VIM DNA methylation detected BE metaplasia with 90.3% sensitivity and 91.7% specificity. Combining the balloon sampling device with molecular assays of CCNA1 plus VIM DNA methylation enables an efficient, well-tolerated, sensitive, and specific method of screening at-risk populations for BE.

Association Between Germline Mutation in VSIG10L and Familial Barrett Neoplasia

Importance Esophageal adenocarcinoma and its precursor lesion Barrett esophagus have seen a dramatic increase in incidence over the past 4 decades yet marked genetic heterogeneity of this disease has precluded advances in understanding its pathogenesis and improving treatment. Objective To identify novel disease susceptibility variants in a familial syndrome of esophageal adenocarcinoma and Barrett esophagus, termed familial Barrett esophagus, by using high-throughput sequencing in affected individuals from a large, multigenerational family. Design, Setting, and Participants We performed whole exome sequencing (WES) from peripheral lymphocyte DNA on 4 distant relatives from our multiplex, multigenerational familial Barrett esophagus family to identify candidate disease susceptibility variants. Gene variants were filtered, verified, and segregation analysis performed to identify a single candidate variant. Gene expression analysis was done with both quantitative real-time polymerase chain reaction and in situ RNA hybridization. A 3-dimensional organotypic cell culture model of esophageal maturation was utilized to determine the phenotypic effects of our gene variant. We used electron microscopy on esophageal mucosa from an affected family member carrying the gene variant to assess ultrastructural changes. Main Outcomes and Measures Identification of a novel, germline disease susceptibility variant in a previously uncharacterized gene. Results A multiplex, multigenerational family with 14 members affected (3 members with esophageal adenocarcinoma and 11 with Barrett esophagus) was identified, and whole-exome sequencing identified a germline mutation (S631G) at a highly conserved serine residue in the uncharacterized gene VSIG10L that segregated in affected members. Transfection of S631G variant into a 3-dimensional organotypic culture model of normal esophageal squamous cells dramatically inhibited epithelial maturation compared with the wild-type. VSIG10L exhibited high expression in normal squamous esophagus with marked loss of expression in Barrett-associated lesions. Electron microscopy of squamous esophageal mucosa harboring the S631G variant revealed dilated intercellular spaces and reduced desmosomes. Conclusions and Relevance This study presents VSIG10L as a candidate familial Barrett esophagus susceptibility gene, with a putative role in maintaining normal esophageal homeostasis. Further research assessing VSIG10L function may reveal pathways important for esophageal maturation and the pathogenesis of Barrett esophagus and esophageal adenocarcinoma.

Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas

Familial aggregation and segregation analysis studies have provided evidence of a genetic basis for esophageal adenocarcinoma (EAC) and its premalignant precursor, Barretts esophagus (BE). We aim to demonstrate the utility of linkage analysis to identify the genomic regions that might contain the genetic variants that predispose individuals to this complex trait (BE and EAC).

118 Identification of a Novel Germ-Line Variant in an Uncharacterized Gene, FBE-1, and Its Putative Role in Familial Barrett's Esophagus

Background and Aim: An early event in the pathogenesis of eosinophilic esophagitis (EoE) is food antigen penetration of esophageal epithelium, but the precise relationship of eosinophilia, dilated intercellular spaces (DIS) and decreased barrier function is unclear. The aim of this study was to determine the correlation and accuracy of site-specific mucosal impedance (MI) measurement of ion flux with esophageal histology in distinguishing active from inactive EoE. Methods: In this study, 10 patients each with active and inactive EoE underwent MI measurement and mucosal biopsies at four esophageal sites (2, 5,10,15cm above the Zline). MI was compared to 10 control patients without esophageal symptoms. Data were analyzed by comparing MI values, Eos/HPF and DIS grade in the three groups at each level examined. Results: The esophageal MI values (ohms) were significantly lower in active when compared to inactive and control patients (1909 vs. 4349 and 5530 ohms, resp., p<.001). (Table) Four active patients had biopsies with eos< 15/HPF with lower DIS grade. There were significant and inverse correlations between MI and eos/HPF as well as DIS (rs=.584 and -.531, respectively, p<.001). Furthermore, MI cut off of 2300 ohms demonstrated 90% sensitivity and 91% specificity for diagnosis of active EoE and 89% and 82% for high grade DIS. Conclusions: In EoE, eosinophil eosinophilia and DIS correlate to MI measured ionic conductance and by inference barrier function. Endoscopic MI measurement in the esophagus is a promising, safe and easy to perform means to assess disease activity in diseases such as EoE. Impedance measurements in EoE patients and controls

Sa1826 Predicting Barrett's Esophagus in Families of Patients With Barrett's Esophagus: A BETRNet Model Fitting Clinical Data to a Genetic Paradigm

Predicting Barretts Esophagus in Families of Patients With Barretts Esophagus: A BETRNet Model Fitting Clinical Data to a Genetic Paradigm Xiangqing Sun, Amitabh Chak, Gary W. Falk, William M. Grady, Margaret F. Kinnard, sumeet K. mittal, Marcia I. Canto, Nicholas J. Shaheen, Jean S. Wang, Prasad G. Iyer, Julian A. Abrams, Joseph Willis, Sanford Markowitz, Jill Barnholtz-Sloan, Wendy Brock, Robert Elston