Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 302914006; ICD10CM: K22.7, K22.70; ICD9CM: 530.85; ORPHA: 99976; DO: 9206;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8p22 | Barrett esophagus/esophageal adenocarcinoma | 614266 | 3 | MSR1 | 153622 | |
| 8q22.3 | Barrett esophagus/esophageal adenocarcinoma | 614266 | 3 | CTHRC1 | 610635 | |
| 10q22.1 | Barrett esophagus/esophageal adenocarcinoma | 614266 | 3 | ASCC1 | 614215 |
A number sign (#) is used with this entry because rare germline mutations have been found in the MSR1 (153622), ASCC1 (614215), and CTHRC1 (610635) genes in patients with Barrett esophagus and/or esophageal adenocarcinoma.
Barrett esophagus, or Barrett metaplasia, describes the phenotypic change of normal esophageal squamous epithelium to a columnar and intestinal-type epithelium. This metaplastic change is important because patients with Barrett esophagus have an increased risk of esophageal adenocarcinoma. The main cause of Barrett metaplasia is gastroesophageal reflux (GER; 109350). The retrograde movement of acid and bile salts from the stomach into the esophagus in this disease causes prolonged injury to the esophageal epithelium and induces chronic esophagitis, which in turn is believed to trigger the pathologic changes (summary by Wong et al., 2005).
Barrett (1950) described a patient with chronic ulcerating esophagitis in which columnar rather than squamous epithelium surrounded the ulcers. Allison and Johnstone (1953), followed by many others, showed that the columnar epithelium-lined intrathoracic structure is anatomically and functionally esophagus. The proximal esophagus usually retains its normal squamous epithelium. The Barrett esophagus is a complication of gastroesophageal reflux. Why it develops only in some patients is not clear; Sjogren and Johnson (1983) suggested that it 'may be congenitally determined in part.' Familial occurrence was reported by Borrie and Goldwater (1976). Adenocarcinoma of the esophagus has an incidence of about 10% in the Barrett esophagus. Adenocarcinoma constitutes a minority of esophageal cancers but most of these originate in a Barrett esophagus.
Gelfand (1983) reported Barrett esophagus in identical twins. Everhart et al. (1978, 1983) described Barrett esophagus in 3 persons in 2 generations of a family.
Crabb et al. (1985) described a family in which the proband had both GER and Barrett esophagus, 3 of 5 children also had both, the other 2 children had only GER, and 2 grandchildren had GER. One of the children with both developed adenocarcinoma of the esophagus.
McKusick (1986) stated that he had seen adenocarcinoma of the esophagus in a man with the Barrett anomaly whose brother died of esophageal cancer.
Prior and Whorwell (1986) observed 2 affected sisters, each of whom presented at age 66.
Jochem et al. (1992) described a family with 6 cases of Barrett esophagus, all in males, in 3 successive generations. In 3 of the patients there was associated adenocarcinoma.
Cameron (1992) reviewed the literature on the genetics of Barrett esophagus.
Drovdlic et al. (2003) studied a large series of families with Barrett esophagus and esophageal adenocarcinoma in search of evidence that a subset of this combination is the result of a hereditary predisposition. Studying 957 individuals in 70 families, 173 had a reported diagnosis of Barrett esophagus or carcinoma of the esophagus or esophagogastric junction: 101 had Barrett esophagus only, 52 had carcinoma of the esophagus and esophagogastric junction, and 20 had both Barrett esophagus and carcinoma. There were 133 affected males and 40 affected females, for a male:female ratio of 3.3:1. In 124 participants (12.9%), a cancer other than esophageal was reported. Of these, 15 had a diagnosis of Barrett esophagus or esophageal carcinoma and 109 did not.
In endoscopic tissue biopsies, Wong et al. (2005) found that CDX1 (600746) mRNA and protein were universally expressed in all samples of Barrett metaplasia (BM) tested but not in normal esophageal squamous or gastric body epithelia. They attributed this tissue-specific expression pattern to the methylation status of the CDX1 promoter, which was completely methylated in normal squamous and gastric epithelia but demethylated in a majority of DNA clones from BM tissue. Conjugated bile salts and the inflammatory cytokines TNF-alpha (191160) and IL1-beta (147720) increased CDX1 mRNA expression via the NFKB (see 164011) pathway in vitro, but only when the CDX1 promoter was unmethylated or partially methylated. Wong et al. (2005) suggested that CDX1 is the molecular link between the etiologic agents that cause BM and the induction of an intestinal phenotype, and that CDX1 promoter demethylation is the key trigger for the development of BM.
In a study of 116 patients of European descent with Barrett esophagus and/or esophageal adenocarcinoma, Orloff et al. (2011) identified rare germline mutations in 3 different genes. Candidate genomic regions were studied after being identified by genomewide linkage analysis of 21 concordant and 11 discordant sib pairs with the disorders. A mutation in the MSR1 gene on chromosome 8p22 (R293X; 153622.0001) was found in 8 (6.9%) patients in the initial cohort and in 2 (3.4%) of 58 patients in a replication study. A second MSR1 mutation (L254V; 153622.0003) was found in 2 patients (1.7%) in the initial cohort. A mutation in the CTHRC1 gene on 8q22 (Q44P; 610635.0001) was found in 1 (1.1%) patient in the initial cohort and in 1 (1.7%) in the replication cohort, and a mutation in the ASCC1 gene on 10q22 (N290S; 614215.0001) was found in 2 (2.1%) patients in the initial cohort.
Associations Pending Confirmation
The Esophageal Adenocarcinoma Genetics Consortium and Wellcome Trust Case Control Consortium (2012) presented the first genomewide association study of Barrett esophagus susceptibility comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at 2 loci were associated with disease risk: rs9257809 on chromosome 6p21, within the MHC locus (combined p = 4.09 x 10(-9); OR = 1.21; 95% CI, 1.13-1.28); and rs9936833 on chromosome 16q24 (combined p = 2.74 x 10(-10); OR = 1.14; 95% CI, 1.10-1.19). The SNP rs9936833 resides 141 kb centromeric to FOXF1 (601089), a forkhead transcription factor in the hedgehog signaling pathway that has a role in the development of the gastrointestinal tract and has been reported to cause esophageal structural alterations when inactivated. The region around rs9936833 contains multiple binding sites for specific transcription factors, such as FOXP2 (605317), that control FOXF1 expression. The SNP rs9257809 lies on the telomeric edge of the MHC region.
Allison, P. R., Johnstone, A. S. The esophagus lined with gastric mucous membrane. Thorax 8: 87-101, 1953. [PubMed: 13077502] [Full Text: https://doi.org/10.1136/thx.8.2.87]
Barrett, N. R. Chronic peptic ulcer of the oesophagus and esophagitis. Brit. J. Surg. 38: 175-182, 1950. [PubMed: 14791960] [Full Text: https://doi.org/10.1002/bjs.18003815005]
Borrie, J., Goldwater, L. Columnar cell-lined esophagus: assessment of etiology and treatment: a 22-year experience. J. Thorac. Cardiovasc. Surg. 71: 825-834, 1976. [PubMed: 1271833]
Cameron, A. J. Barrett's esophagus and adenocarcinoma: from the family to the gene. (Editorial) Gastroenterology 102: 1421-1424, 1992. [PubMed: 1551552] [Full Text: https://doi.org/10.1016/0016-5085(92)90789-2]
Crabb, D. W., Berk, M. A., Hall, T. R., Conneally, P. M., Biegel, A. A., Lehman, G. A. Familial gastroesophageal reflux and development of Barrett's esophagus. Ann. Intern. Med. 103: 52-54, 1985. [PubMed: 4003988] [Full Text: https://doi.org/10.7326/0003-4819-103-1-52]
Drovdlic, C. M., Goddard, K. A. B., Chak, A., Brock, W., Chessler, L., King, J. F., Richter, J., Falk, G. W., Johnston, D. K., Fisher, J. L., Grady, W. M., Lemeshow, S., Eng, C. Demographic and phenotypic features of 70 families segregating Barrett's oesophagus and oesophageal adenocarcinoma. J. Med. Genet. 40: 651-656, 2003. Note: Erratum: J. Med. Genet. 41: 46 only, 2004. [PubMed: 12960209] [Full Text: https://doi.org/10.1136/jmg.40.9.651]
Esophageal Adenocarcinoma Genetics Consortium, Wellcome Trust Case Control Consortium. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus. Nature Genet. 44: 1131-1136, 2012. [PubMed: 22961001] [Full Text: https://doi.org/10.1038/ng.2408]
Everhart, C. W., Holtzapple, P. G., Humphries, T. J. Barrett's esophagus: inherited epithelium or inherited reflex? (Editorial) J. Clin. Gastroent. 5: 357-358, 1983. [PubMed: 6886360]
Everhart, C. W., Jr., Holtzapple, P. G., Humphries, T. J. Occurrence of Barrett's esophagus in three members of the same family: first report of familial incidence. (Abstract) Gastroenterology 74: 1032 only, 1978.
Gelfand, M. D. Barrett's esophagus in sexagenarian identical twins. J. Clin. Gastroent. 5: 251-253, 1983. [PubMed: 6683290] [Full Text: https://doi.org/10.1097/00004836-198306000-00011]
Jochem, V. J., Fuerst, P. A., Fromkes, J. J. Familial Barrett's esophagus associated with adenocarcinoma. Gastroenterology 102: 1400-1402, 1992. [PubMed: 1551547]
Lagergren, J., Bergstrom, R., Lindgren, A., Nyren, O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. New Eng. J. Med. 340: 825-831, 1999. [PubMed: 10080844] [Full Text: https://doi.org/10.1056/NEJM199903183401101]
McKusick, V. A. Personal Communication. Baltimore, Md. 1986.
Mossberg, S. M. The columnar-lined esophagus (Barrett syndrome)--an acquired condition? Gastroenterology 50: 671-676, 1966. [PubMed: 5935228]
Orloff, M., Peterson, C., He, X., Ganapathi, S., Heald, B., Yang, Y., Bebek, G., Romigh, T., Song, J. H., Wu, W., David, S., Cheng, Y., Meltzer, S. J., Eng, C. Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma. JAMA 306: 410-419, 2011. [PubMed: 21791690] [Full Text: https://doi.org/10.1001/jama.2011.1029]
Prior, A., Whorwell, P. J. Familial Barrett's oesophagus? Hepatogastroenterology 33: 86-87, 1986. [PubMed: 3721391]
Sjogren, R. W., Jr., Johnson, L. F. Barrett's esophagus: a review. Am. J. Med. 74: 313-321, 1983. [PubMed: 6337489] [Full Text: https://doi.org/10.1016/0002-9343(83)90635-6]
Wong, N. A. C. S., Wilding, J., Bartlett, S., Liu, Y., Warren, B. F., Piris, J., Maynard, N., Marshall, R., Bodmer, W. F. CDX1 is an important molecular mediator of Barrett's metaplasia. Proc. Nat. Acad. Sci. 102: 7565-7570, 2005. [PubMed: 15894614] [Full Text: https://doi.org/10.1073/pnas.0502031102]