Earlier age of disease onset is generally considered to be an indicator of genetic susceptibility to disease. In our previous study of a smaller cohort, when we examined age of cancer diagnosis in our entire FBE and non-familial cohorts, we failed to identify a difference in age of cancer diagnosis between familial and non-familial cancers.(7
) However, in this study, once we restricted ourselves to investigating the smaller subset of multiplex FBE kindreds with 3 or more members with BE, EAC, or EGJAC, we discovered that EAC is diagnosed at a significantly earlier age in these FBE kindreds when compared to duplex and non-familial kindreds. This finding is supported by mixed modeling accounting for familial correlations, with a p-value of 0.028. These results, which support a genetic basis for FBE, at least in multiplex kindreds, are also consistent with our previous segregation analysis.(8
) The results of this study also suggest that individuals who are members of multiplex FBE pedigree and are candidates for endoscopic screening (3
) may be considered for screening at an earlier age than the general population.
Multiplex kindreds also differed significantly from duplex and non-familial kindreds in terms of risk factors associated with BE and EAC. The proportion of individuals reporting heartburn, which is the most common symptom of GERD, was not different, although proportion of individuals with regurgitation was lower. Other risk factors such as high BMI and smoking, which have been positively associated with BE and EAC in previous studies, were inversely associated with multiplex FBE kindreds, suggesting that familial aggregation of BE and its associated cancers is not related to a common exposure to these environmental factors in family members. Absence of other known risk factors in subjects with FBE also makes it more likely that a currently unrecognized, and possibly genetic, factor is operative in these subjects.
The definition of BE in this cohort was quite rigorous and excluded intestinal metaplasia associated with carditis. Conversely, our definition of the FBE trait was broad and included BE and EAC because evidence suggests that nearly all EAC develop from BE. (12
) We followed the recent TNM Classification that now stages EGJAC similar to EAC. (18
) Interestingly, all but one of the cancers in the multiplex FBE kindreds were EAC’s suggesting that for the purpose of genetic studies it may be prudent to restrict the trait to rigorously defined BE and EAC. This study also found that cancers in multiplex FBE kindreds were not diagnosed at an earlier stage and in fact the results suggest that these cancers may be more advanced at diagnosis. Although we did not have direct data on which cancers were diagnosed as a result of endoscopic screening or surveillance, this finding reassures us that the early age of cancer diagnosis in these multiplex kindreds is not related to awareness of disease and early medical care seeking behavior in these families.
In other complex diseases, genetic predisposition is manifested strongly in families with 3 or more affected individuals. For example, the risk of pancreatic cancer is not significantly increased in families with 2 members with pancreatic cancer but is significantly increased in families with 3 or more members with the disease.(19
) Similarly, an individual’s risk for colon neoplasias is increased depending on the number of relatives with colon adenomas or colon cancers.(20
) Familial cancer syndromes are often also associated with cancers of other organs. This study did not find an association between FBE and other cancers in general. There was a significant association between multiplex FBE and lung, bone and liver cancer, but the number of subjects reporting these cancers in the present study was small. Also, cancer in these sites is frequently metastatic, and given our inability to perform complete review of the entire medical records of all subjects, this information could be inaccurate. Our database is limited to information obtained from family members who choose to participate and, because of inability to verify their complete medical record, we have relied on self-reported diagnoses of other cancers. Many family members chose not to participate, and differential participation due to chance or diminished survival in cancer sufferers could easily miss an association between FBE and other cancers. However, we speculate that another reason could be that FBE is caused specifically by genetic variants that predispose to an injury to the esophagus or the development of intestinal metaplasia rather than a more general cancer susceptibility gene.
This study should be interpreted within the limitations of the study design. We had tested the hypothesis that FBE is associated with an earlier age of cancer diagnosis in our previous study and had not found an effect.(7
) By increasing our power with an expanded cohort, we were able to discern an effect in multiplex kindreds with the familial group definitions offered in this study. In this re-analysis of these data, the highly significant p-values showing marked differences between multiplex kindreds and other BE/EAC/EGJAC kindreds suggest that these differences are not artifactual. Due to the possibility of lead-time bias, this finding may warrant further replication. The database is missing information on several variables for a number of study subjects: missing data on deceased relatives with cancer could bias our results, especially since some age of cancer diagnosis information was collected from proxies. It is unlikely that proxy respondents would systematically misclassify a younger age of cancer diagnosis in multiplex FBE kindreds, as opposed to duplex or non-familial kindreds. As in previous studies,(6
) we used obesity 1 year prior to diagnosis for analysis, assuming that the majority of weight loss associated with cancer diagnosis was within the first year prior to diagnosis. Overweight individuals underreport weight, which could have lead to an underestimation of obesity.(22
) As in our previous study, mulitvariable mixed linear models were used to adjust for familial correlations because they allow the specification of and accounting for family correlation structure in our univariable and multivariable models.(7
) Although a statistically-significant difference in BMI was identified, the biological significance of <1 kg/m2
is unknown. It is likely that individuals in this study without a genetic susceptibility were misclassified as FBE, especially in the duplex kindreds and others with a genetic susceptibility were misclassified as non-familial because we had insufficient information on the family or the family size was small. However, these misclassifcations would only attenuate differences between multiplex FBE kindreds and non-familial cases. Of course, true differences in age of cancer diagnosis can only be measured once the genetic variants in multiplex FBE kindreds have been identified. Finally, the diagnosis of EAC in a family member might precipitate a lower threshold for evaluation of GERD symptoms, and perhaps an earlier diagnosis of EAC than might happen in sporadic cases. However, this bias seems less likely given that multiplex families with an EAC proband did not have a lower mean age of diagnosis than multiplex families with a BE proband, as might be expected if cancer fear precipitated earlier diagnosis. Also, as noted above, cancers diagnosed in multiplex families were not of earlier stage than those diagnosed duplex or non-FBE families.
To summarize, the results of this analysis indicated that EAC is diagnosed at an earlier age in multiplex FBE kindreds and might be more advanced at time of diagnosis. Along with the results of our prior segregation analysis,(8
) which indicates that FBE is caused by an incompletely penetrant autosomally dominant genetic variant, the results of the present study argue strongly for investigations into the genetic basis of FBE. Such investigations should focus on FBE kindreds with 3 or more members affected with rigorously defined BE and EAC phenotypes, because these kindreds have the strongest epidemiological evidence for a genetic basis. The study results also suggest that screening practices may need to be modified for an earlier age in these multiplex FBE kindreds.