Obesity is increasingly recognized as an important risk factor for the development of Barrett’s esophagus (BE) and its associated adenocarcinomas, which could partially explain the rising incidence of these diseases in the United States and other countries. 7–10,19–22
Although obesity also contributes to gastro-esophageal reflux,23–25
obesity is clearly an independent risk factor for EAC.7–10
Central adiposity has also recently been shown to be independently associated with BE. 19–22
In this study, obesity 1 year previous to diagnosis of cancer was significantly associated with a diagnosis of cancer at an earlier age. This association was further strengthened after adjustment for heartburn and regurgitation symptom duration. In contrast, the duration of GERD symptoms by themselves were not significant predictors of earlier age of cancer diagnosis. In addition, other known BE/EAC risk factors such as male gender, white race, and smoking were not significantly associated with family history or earlier age at cancer diagnosis.
The association of obesity with earlier age of cancer diagnosis could be related to a dietary factor, obesity induced gastro-esophageal reflux, or alterations in metabolic mediators. Obesity has been proposed to be carcinogenic for a variety of cancers.26
General molecular mechanisms for obesity induced carcinogenesis include oxidative stress/DNA damage, non-inflammatory changes in immune function, inflammatory mediators, hormones and growth factors, and metabolic detoxification factors. The specific molecular mechanisms that lead to the development of esophageal and gastroesophageal junctional cancers at an earlier age in the presence of obesity need to be elucidated.
Familial aggregation often implies a genetic susceptibility to disease but may also be caused by a common environmental exposure within families. In general, familial cancers are presumed to be complex genetic traits, which in some cancers may manifest with an early age of disease onset. The manifestation of a putative susceptibility gene depends on trait definition. Inclusion of Barrett’s esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastro-esophageal junction as part of a single complex trait is justified because of strong evidence that nearly all adenocarcinomas of the esophagus and a substantial proportion of adenocarcinomas of the gastro-esophageal junction arise in Barrett’s epithelium.1–2,4,27–32
This study demonstrates that age of disease onset for FBE cancers is the same as non-FBE cancers.
Familial aggregation of BE and its associated cancers could represent a genetic susceptibility to metaplastic transformation of the esophagus, a genetic susceptibility to a recognized risk factor such as GERD1–4
or a common environmental exposure such as smoking or alcohol.33–35
The proportion of FBE cancers reporting GERD symptoms was the same as the proportion of non-FBE cancers with GERD symptoms, suggesting that FBE does not represent a genetic predisposition to gastro-esophageal reflux. Our prior study that measured the prevalence of FBE raised the possibility that FBE probands with cancer may be less obese than non-FBE probands with cancer.12
However, the present study, which had a larger sample size and included additional relatives of probands as well as probands did not find a significant difference. Thus, FBE is unlikely to represent a genetic susceptibility to obesity. Finally, this study also found no difference in smoking or alcohol use between FBE and non-FBE cancers.
GERD is clearly associated with BE and its associated cancers.1–4
Chronic gastroesophageal reflux is believed to be essential to the process of metaplastic transformation. However, it is not clear what role persistent gastroesophageal reflux plays in the progression from metaplasia to cancer once metaplasia has developed. The duration of GERD symptoms was not found to be associated with an earlier age of cancer diagnosis in this study. The study was primarily powered to investigate the association of age of cancer diagnosis with familiality. It might not have sufficient power to detect an association with GERD. GERD symptoms are also an indirect marker of GERD exposure and might not reflect the extent of exposure. Another possible explanation that needs to be explored is that although GERD plays an important role in the process of metaplastic transformation it is less important in the subsequent progression to cancer.
The results of this study need to be interpreted in the context of the limitations of the study design. Data on several variables were missing (smoking and alcohol history were unavailable in nearly a third of the subjects) for a number of study subjects (see ). Missing data could lead to biased results, especially if there was a unrecognized systematic misclassification of exposures reported by proxy respondents. However, it is unlikely that age of cancer diagnosis would be misreported, even by proxy respondents. Obesity 1 year prior to diagnosis or longer was used for analysis on the assumption that the majority of weight loss associated with cancer diagnosis was within the first year prior to diagnosis. Obesity was assessed by calculated BMI but we had no information on central adiposity, which may be a better measure of the type of obesity that predisposes individuals to BE.19–22
Individuals self reported data collected by the FBE questionnaire including height and weight in the years preceding study enrollment. Overweight individuals are known to underreport weight, which might lead to an underestimation of obesity in this study.36
Data on GERD symptoms were also self reported and were collected using questions from the validated Mayo GERQ developed by Locke et al.17
This study cohort of cancer patients is part of an ongoing family study. Therefore, it was necessary to adjust for familial correlations in the statistical analysis. Subjects with a reported affected relative whose diagnosis could not be verified despite multiple attempts were classified as part of the FBE group because we have found the false positive rate of reported family history to be less than 10%.12
The results did not change when the analysis was restricted to the subset of FBE patients in whom the diagnosis in the affected relative was confirmed (). The results also did not change if adenocarcinomas of the gastro-esophageal junction were excluded from analysis (data not shown). Probands and relatives were able to provide information about age of cancer diagnosis for deceased relatives with cancer; however, exposure information was generally missing for these deceased individuals. Complex traits such as FBE may be genetically heterogeneous. Until and unless the genetic variant(s) that confers susceptibility to the development of BE is(are) identified, there is a strong likelihood that some individuals in this study without a genetic susceptibility were misclassified as FBE and others with a genetic susceptibility were misclassified as non-FBE (“apparently sporadic”). The sample size was sufficient for at least a 20% rate of misclassification. Of course, there may be selected variants that are manifested at an earlier age. Therefore, if FBE is truly a complex genetic disease, it is unlikely that any major susceptibility gene is manifested at an earlier age.
In summary, this study found that obesity was associated with earlier age of cancer diagnosis. The molecular mechanisms by which obesity contributes to the development of BE and its progression to cancer need to be investigated. There were no significant differences in age of disease onset and other risk factors between FBE and non-FBE cancers. Within the limitations of unmeasurable misclassification, FBE is unlikely to represent a genetic susceptibility to obesity or gastro-esophageal reflux. The trait is proposed to be a manifestation of genetic variant(s) that confer a susceptibility to metaplastic transformation of the esophageal epithelium perhaps in the presence of inflammation caused by gastro-esophageal reflux and/or obesity. Furthermore, obesity might contribute to the progression of BE to cancer by undefined mechanisms in susceptible individuals. Based on the results of this study, screening and surveillance practices do not need to be modified for age in individuals who are members of FBE families.