Genetic Determinants of Barrett's Esophagus and Esophageal Adenocarcinoma (FBE)

General Description

Previous studies have shown an aggregation of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) (including esophagastric junctional adenocarcinoma [EGJAC]) in families, a syndrome that has been termed Familial Barrett’s esophagus (FBE). This aggregation, which suggests a biological relationship between BE and EAC, may be caused by common environmental exposures in family members, a genetic predisposition to disease, or both. For complex diseases such as BE and cancer, genetic influences may be more evident in pedigrees that have 3 or more affecteds. Thus, the Familial Barrett’s Esophagus study was established by the Familial Barrett’s Esophagus Consortium (FBEC) to determine whether cancers develop at an earlier age in multiplex Familial Barrett’s Esophagus (FBE) kindreds, defined as 3 or more members affected by Barrett’s esophagus (BE) or esophageal adenocarcinoma (EAC). Ultimately, the study aims to identify putative susceptibility genes for BE and its associated cancers.

Individuals with BE, EAC, or EGJAC were recruited at 8 academic care centers participating in the FBEC. After providing informed consent, participants were enrolled and given a self-administered FBE questionnaire. Information was collected on gastroesophageal reflux symptoms; risk factors such as age, gender, race, and self-reported obesity measures; and family history of BE, EAC, stomach and throat cancer (which may be incorrect ways of reporting esophageal cancer). Probands, defined as the first known affected member in a family, had the opportunity to discuss and clarify family history with their relatives before mailing back the questionnaire. Pedigrees were constructed from the questionnaire. Differences in the age of diagnosis and other variables of interest, such as gender, obesity, race, acid regurgitation, heartburn, smoking and alcohol consumption, were assessed between the three family groups (non-familial, duplex and multiplex). Only probands and kindreds with a confirmed diagnosis were included in the analysis.

The study found that EAC is diagnosed at a significantly earlier age in multiplex FBE kindreds when compared to duplex and non-familial kindreds. Findings suggest that individuals who are members of multiplex FBE pedigree may be considered for screening at an earlier age than the general population. Following that earlier age of disease onset is considered an indicator of genetic susceptibility to disease, these results support a genetic basis for FBE. Future investigations into the genetic basis of FBE are needed and should focus on FBE kindreds with 3 or more members affected with defined BE and EAC phenotypes.

Objectives

The study aims to determine whether cancers develop at an earlier age in multiplex Familial Barrett’s Esophagus (FBE) kindreds, defined by 3 or more members affected by Barrett’s esophagus (BE) or esophageal adenocarcinoma (EAC). The ultimate objective of the study is to identify putative susceptibility genes for BE and its associated cancers.

Outcome Measure

Differences in the age of diagnosis and other variables of interest, such as gender, obesity, race, acid regurgitation, heartburn, smoking and alcohol consumption, were assessed between the three family groups (non-familial, duplex and multiplex).

Criteria

Individuals with clear documentation of BE or EAC and their family members were eligible for the study. Documentation of BE was defined as endoscopic evidence of BE in the tubular esophagus and histological evidence of intestinal metaplasia. Documentation of EAC was defined as a mass predominantly involving the tubular esophagus or the esophagogastric junction with histological evidence of an adenocarcinoma.

Outcome

The study found that EAC is diagnosed at a significantly earlier age in multiplex FBE kindreds when compared to duplex and non-familial kindreds. Findings suggest that individuals who are members of multiplex FBE pedigree may be considered for screening at an earlier age than the general population. Following that earlier age of disease onset is considered an indicator of genetic susceptibility to disease, these results support a genetic basis for FBE. Future investigations into the genetic basis of FBE are needed and should focus on FBE kindreds with 3 or more members affected with defined BE and EAC phenotypes.