Germline APC Mutation and Familial Barrett Esophagus

There has been a striking increase in the incidence of esophageal adenocarcinoma in Western populations over the past several decades. In most cases, esophageal adenocarcinoma is thought to derive from a precursor lesion—Barrett esophagus—through a multistep progression: metaplasia, dysplasia, early adenocarcinoma, and, finally, invasive cancer. Parallel to this histologic progression is a stepwise accumulation of genetic alterations and chromosomal changes. In addition, familial Barrett esophagus has been described when Barrett esophagus, esophageal adenocarcinoma, and/or adenocarcinoma of the gastroesophageal junction occur in multiple family members, purportedly through an autosomal dominant, polygenic inheritance pattern.¹ Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP), a more recently described variant of FAP, are caused by germline mutations in the adenomatous polyposis coli (APC) gene. Tumor development in FAP and AFAP occurs after a somatically acquired “second hit”—according to Knudson's “2-hit” hypothesis—resulting in the loss of the remaining normal APC allele.² Gupta and colleagues present an interesting family with AFAP who have gastroesophageal reflux disease, Barrett esophagus, and/or esophageal adenocarcinoma.³ Although the simultaneous occurrence of these 2 potentially inherited disorders in the same family may be a chance event, this case report raises the possibility that the disorders could be linked.

The increase in esophageal adenocarcinoma over the past several decades implicates 1 or more major environmental factors in its pathogenesis (ie, obesity, gastroesophageal reflux disease). It is possible that changes in environmental factors, together with existing genetic susceptibility factors, contribute to the rising incidence in esophageal adenocarcinoma, as has been suggested with the obesity epidemic in the United States. There have been multiple reports of familial clustering of patients with hiatal hernia, esophagitis, Barrett esophagus, and esophageal adenocarcinoma. These findings have led some investigators to propose a subgroup of patients with familial Barrett esophagus (individuals with more than 1 first- or second-degree relative with long-segment Barrett esophagus or adenocarcinoma of the esophagus or gastroesophageal junction).⁴

In these reports of familial clustering, the prevalence of gastroesophageal reflux disease in relatives of familial Barrett esophagus patients was approximately 40% (vs 20% in sporadic Barrett esophagus).⁵ In a recent study of 20 families, the risk of Barrett esophagus in familial Barrett esophagus patients was estimated to be 20% (vs 10% in sporadic Barrett esophagus patients), with an adenocarcinoma risk of 31% (vs 5% in sporadic Barrett esophagus patients).⁶ Another study found familial Barrett esophagus in 7.3% of patients presenting with Barrett esophagus, esophageal adenocarcinoma, or gastroesophageal junction adenocarcinoma.⁷ Romero and associates found a significantly higher incidence of reflux symptoms and esophagitis in first-degree relatives of Barrett esophagus patients.⁸ Twin studies have consistently shown a higher incidence of reflux symptoms in monozygotic twins compared to dizygotic twins.^9–11 A recent segregation analysis of 881 singly ascertained pedigrees provided epidemiologic evidence in support of 1 or more rare, autosomal dominant susceptibility alleles in familial Barrett esophagus families.¹ The above findings suggest either Mendelian inheritance with markedly reduced penetrance, or a complex disorder with multiple genetic and environmental factors.

If these 2 conditions are linked in the family discussed in the case report by Gupta and coworkers, what is the possible pathogenetic mechanism?³ As Gupta and colleagues note, APC gene mutations in FAP lead to increased β-catenin levels and activation of the Wnt pathway.³ Activation and alteration of the Wnt signaling pathway has been implicated in a broad range of cancers. A recent model of Barrett esophagus and esophageal adenocarcinoma proposed that multiple alterations in Wnt pathway components lead to nuclear accumulation of β-catenin and activation of target genes in Barrett esophagus, which promote progression to esophageal adenocarcinoma.¹² APC promoter hypermethylation is also observed in a high percentage of esophageal adenocarcinoma patients.¹² Although this model proposes a different mechanism of Wnt activation in esophageal adenocarcinoma compared to AFAP/FAP, both conditions lead to increased nuclear β-catenin, with activation of target genes in carcinogenesis.

It appears that some, but not all, extracolonic manifestations of FAP, as well as the AFAP phenotype itself, correlate with specific mutation sites in the APC gene.¹³ Although upper gastrointestinal cancers occur in less than 10% of individuals with FAP or AFAP and have not been found to correlate with specific mutation sites in classic FAP, the AFAP phenotype still has not been fully characterized, and relatively rare associations may not have been noted as of yet.¹⁴ It is possible that the specific mutation in this AFAP family is linked to genetic alterations present in familial Barrett esophagus that have yet to be identified. It has been proposed, although not widely accepted, that genotype-phenotype correlations be used in the management of FAP. Because specific mutations have been associated with the risk of rectal cancer and/or poor prognosis in rectum retention, it has been suggested that the results of genetic testing should be added to the clinical phenotype to assist surgical decision making in FAP.¹⁵

In conclusion, Gupta and associates present an intriguing family with AFAP, gastroesophageal reflux disease, Barrett esophagus, and/or esophageal adenocar-cinoma.³ An association has not been previously noted between either FAP or AFAP and esophageal reflux, Barrett esophagus, or esophageal adenocarcinoma. There appears to be a subgroup of patients with Barrett esophagus or esophageal adenocarcinoma who have an inherited susceptibility termed “familial Barrett esophagus.” The family in this case report certainly fulfills criteria for familial Barrett esophagus, as defined in the literature. Although it is biologically plausible that the esophageal mucosal disease in this family is related to AFAP, it is more likely that the occurrence of 2 rare conditions in the same family is a sheer coincidence. The important clinical message is to ascertain whether other cancers, particularly gastrointestinal cancers or their precursor lesions, are present in family members of patients with colonic polyposis, Barrett esophagus, or esophageal adenocarcinoma to determine whether there is an increased inherited risk and whether screening of other family members is warranted. In the future, different screening recommendations, surveillance regimens, and/or treatments may be based on specific genetic alterations identified as being associated with inherited susceptibility to gastrointestinal cancers. This customization awaits more complete characterization of the natural history of these inherited conditions and identification of the genetic abnormalities present.