EDITORIAL What We Know and What We Need to Know About Familial Gastroesophageal Reflux Disease and Barrett’s Esophagus arrett’s esophagus (BE) is the only known precursor of esophageal adenocarcinoma (EAC), a cancer that continues to carry a poor prognosis.1 The exponential increase in both BE and EAC over the past 4 decades2,3 undoubtedly is related to some, as yet uncharacterized, changing environmental agent. Both BE and EAC arise as a consequence of chronic inflammatory injury to the distal esophagus from gastric refluxate. Although BE and EAC traditionally have been considered environmental diseases, the fact that they occur predominantly in white men is a clue to an underlying genetic susceptibility. Alterations in the environment that have caused an increased incidence of these diseases also have led to the recent recognition of familial aggregation. BE and EAC are now proposed to be complex diseases caused by an interplay of genetic susceptibility with environmental factors that include, but are not limited to, gastroesophageal reflux, diet, central obesity, and smoking.
B
Familial Aggregation of Gastroesophageal Reflux Disease, Barrett’s Esophagus, and Esophageal Adenocarcinoma There is evidence implicating genetic factors, even in the development of gastroesophageal reflux disease (GERD). Two studies, one by Romero et al4 and one by Trudgill et al,5 have shown a significantly increased prevalence of GERD among family members of patients with BE and EAC. The higher concordance of reflux symptoms found in monozygotic twins compared with dizygotic twins with an estimated polygenic heritability of 30% to 40% further strengthens a genetic hypothesis.6–8 However, molecular studies that identify genetic factors to explain familial GERD are awaited. Familial aggregation is the first evidence/recognition of the genetic basis of disease. Numerous case reports starting in the 1970s documented familial clusters of BE and EAC.7,9–12 The prevalence of verified BE within these families was well over 20%, compared with a less than 3% prevalence in the general population.13 The next step in the evidence chain was a hospital-based, case-control study in which we showed aggregation of BE and associated cancers in Caucasian families.14 This phenomenon was termed familial Barrett’s esophagus.15 Subsequently, the prevalence of familial BE in patients with these diseases was estimated to be 6% to 7.3%.16,17 In a follow-up prospective study, we showed that endoscopic screening of relatives of familial BE probands identified new BE
cases. This finding added credence to the familial clustering hypothesis, and also provided practical implications for high-risk screening.18 Familial aggregation must be interpreted cautiously. Aggregation of BE and EAC could be owing to common environmental exposures in families, such as smoking,19,20 diet, a genetic or inherited susceptibility to risk factors such as obesity or GERD,21–23 a genetic susceptibility to the development of metaplastic or neoplastic esophageal epithelium, or a combination of these effects. BE and EAC occur at a younger age in affected members of multiply affected BE families.24,25 Appearance of disease in younger individuals, which normally would not manifest until older ages in sporadic cases, also is supportive of the genetic hypothesis. Based on previous studies,14,24 we postulated that, similar to other metaplastic and neoplastic diseases, the development of Barrett’s epithelium and subsequent adenocarcinomas is caused by complex pathways involving inherited germline mutations and environmentally induced acquired somatic mutations. A study of inheritance patterns in 70 BE families by The Familial Barrett Esophagus Consortium suggested that inheritance of familial BE is autosomal dominant.24 Furthermore, our segregation analysis of 881 familial BE pedigrees provided reasonable epidemiologic evidence in support of the inheritance of one or more rare, autosomal-dominant susceptibility alleles.15 These findings suggest Mendelian inheritance, not necessarily monogenic, with markedly reduced penetrance as a result of environmental factors.
Findings From Genetic Linkage and Genome-Wide Association Studies More recent genetic linkage studies and genome-wide association studies (GWAS) have provided direct evidence of a genetic predisposition. A linkage study followed by a fine mapping association study of familial BE identified association with single nucleotide polymorphisms (SNPs) in the MSR1 (8p), ASCC1 (10q), and CTHRC1 (8q) genes,26 which are involved in macrophage function and inflammatory pathways. A GWAS by the Barrett’s and Esophageal Adenocarcinoma Consortium showed that both BE and EAC are influenced by multiple germline genetic variants of small effect. By using genome-wide genotype data on unrelated cases and controls, as opposed to traditional twin studies of heritability, Barrett’s and Esophageal Adenocarcinoma Consortium investigators measured the array heritability for BE and EAC to be 35% and 25%, respectively.27 They also found a significant polygenic overlap and a strong genetic correlation between BE and EAC, suggesting substantial shared genetic architecture between BE and EAC. Clinical Gastroenterology and Hepatology 2014;-:-–-
2
Sun et al
A large GWAS study, the first of its kind, using unrelated BE cases and controls, identified 2 SNPs on 2 chromosomes, namely 6p21 and 16q24, to be associated significantly with risk of BE.28 The 16q24 is of particular interest because its closest protein coding gene, termed FOXF1, serves as a transcription factor in the hedgehog signaling pathway. FOXF1 has an important role in the development of the foregut during organogenesis.29 It also has been shown that certain FOXF1 variants that are responsible for increased BE risk also increase the risk of EAC in Caucasians.30 A recent unrelated case-control GWAS that looked at EACs as well as BE, in addition to confirming the previous associations with FOXF1 and HLA loci, identified new susceptibility loci on chromosomes 19p, 9q, and 3p, in the region of genes associated with oncogenic activity and transcription factors in esophageal specification and esophageal development.31 The finding that the previously identified Barrett’s esophagus association locus also has a role in EAC risk suggests that much of the genetic basis for EAC lies in the development of BE. These associations have provided direct evidence that BE has a genetic component, and imply that we may be close to finding important pathways in the development of BE and EAC. Future linkage and GWAS studies that concentrate on familial Barrett’s esophagus in multiplex Barrett’s families may identify new genetic susceptibility variants because of the increased genetic components in such samples. The study by Verbeek et al32 in this issue adds to the growing evidence for the familiality of BE and EAC. They studied a large European cohort of 838 index patients with BE or EAC and their relatives by administering questionnaires. A diagnosis of familial BE was made after histologic confirmation of intestinal metaplasia in 1 or more first- or second-degree relatives of the index patient. The prevalence of familial BE was found to be 7%, consistent with previous results in US populations,16,17 They also found familial BE cases to have a significantly younger age of onset of heartburn and EAC diagnosis than nonfamilial cases, and reflux symptoms were reported more frequently among first-degree relatives of familial BE cases than those of nonfamilial BE cases—not only strengthening the earlier reports of younger affection status in familial BE,24,25 but also consistently supporting the genetic hypothesis of GERD, BE, and EAC.
Inferences and Conclusions Advances have been made over the past decade in our understanding of genetic and environmental factors associated with GERD, BE, and EAC, which can guide the development of risk prediction models in populations and families. Genetic susceptibility variants of BE identified in epidemiologic studies need to be validated further by functional analysis, and more susceptibility genes probably remain to be discovered by more powerful
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
approaches such as by studying more genetically informative samples. The complexity of familial BE suggests we need further studies to determine the genetic causal variants and explain the mechanisms by which these variants control the development of BE and EAC. There are several regression models developed to predict BE and EAC risk in case-control populations with moderate prediction accuracy.33–35 New screening and prediction tools with better performance to predict risk, especially in BE families, are needed, however, unless based on known causal mechanisms, a model cannot be expected to apply to populations other than the one in which it was estimated. The discovery of SNPs at major loci of gene transcription that are known to play a role in metaplastic and dysplastic changes show that we are closer than ever before to finding the genes associated with BE and EAC. Assessing individual genetic susceptibility may help target high-risk patients for endoscopic screening programs rather than using a cost-ineffective, population-wide approach. XIANGQING SUN, PhD Division of Epidemiology and Biostatistics Case Western Reserve University Cleveland, Ohio APOORVA KRISHNA CHANDAR, MBBS, MA, MPH Division of Gastroenterology and Hepatology Case Western Reserve University Cleveland, Ohio ROBERT ELSTON, PhD Division of Epidemiology and Biostatistics Case Western Reserve University Cleveland, Ohio AMITABH CHAK, MD Division of Gastroenterology and Hepatology Case Western Reserve University Cleveland, Ohio
References 1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9–29. 2. Simard EP, Ward EM, Siegel R, et al. Cancers with increasing incidence trends in the United States: 1999 through 2008. CA Cancer J Clin 2012;62:118–128. 3. Thrift AP, Whiteman DC. The incidence of esophageal adenocarcinoma continues to rise: analysis of period and birth cohort effects on recent trends. Ann Oncol 2012;23:3155–3162. 4. Romero Y, Cameron AJ, Locke GR 3rd, et al. Familial aggregation of gastroesophageal reflux in patients with Barrett’s esophagus and esophageal adenocarcinoma. Gastroenterology 1997;113:1449–1456. 5. Trudgill NJ, Kapur KC, Riley SA. Familial clustering of reflux symptoms. Am J Gastroenterol 1999;94:1172–1178. 6. Mohammed I, Cherkas LF, Riley SA, et al. Genetic influences in gastro-oesophageal reflux disease: a twin study. Gut 2003; 52:1085–1089.
-
2014
7. Gelfand MD. Barrett esophagus in sexagenarian identical twins. J Clin Gastroenterol 1983;5:251–253. 8. Cameron AJ, Lagergren J, Henriksson C, et al. Gastroesophageal reflux disease in monozygotic and dizygotic twins. Gastroenterology 2002;122:55–59. 9. Everhart CW, Holtzapple PG, Humphries TJ. Occurrence of Barrett’s esophagus in three members of the same family: first report of familial incidence. Gastroenterology 1978;74:A1032. 10. Prior A, Whorwell PJ. Familial Barrett’s oesophagus? Hepatogastroenterology 1986;33:86–87. 11. Eng C, Spechler SJ, Ruben R, et al. Familial Barrett esophagus and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol Biomarkers Prev 1993;2:397–399. 12. Poynton AR, Walsh TN, O’Sullivan G, et al. Carcinoma arising in familial Barrett’s esophagus. Am J Gastroenterol 1996; 91:1855–1856. 13. Ronkainen J, Aro P, Storskrubb T, et al. Prevalence of Barrett’s esophagus in the general population: an endoscopic study. Gastroenterology 2005;129:1825–1831. 14. Chak A, Lee T, Kinnard MF, et al. Familial aggregation of Barrett’s oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults. Gut 2002;51:323–328. 15. Sun X, Elston R, Barnholtz-Sloan J, et al. A segregation analysis of Barrett’s esophagus and associated adenocarcinomas. Cancer Epidemiol Biomarkers Prev 2010;19:666–674. 16. Chak A, Ochs-Balcom H, Falk G, et al. Familiality in Barrett’s esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol Biomarkers Prev 2006;15:1668–1673. 17. Ash S, Vaccaro BJ, Dabney MK, et al. Comparison of endoscopic and clinical characteristics of patients with familial and sporadic Barrett’s esophagus. Dig Dis Sci 2011;56:1702–1706.
Editorial
3
23. Singh S, Sharma AN, Murad MH, et al. Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and metaanalysis. Clin Gastroenterol Hepatol 2013;11:1399–1412.e7. 24. Drovdlic CM, Goddard KA, Chak A, et al. Demographic and phenotypic features of 70 families segregating Barrett’s oesophagus and oesophageal adenocarcinoma. J Med Genet 2003;40:651–656. 25. Chak A, Chen Y, Vengoechea J, et al. Variation in age at cancer diagnosis in familial versus nonfamilial Barrett’s esophagus. Cancer Epidemiol Biomarkers Prev 2012;21:376–383. 26. Orloff M, Peterson C, He X, et al. Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma. JAMA 2011;306:410–419. 27. Ek WE, Levine DM, D’Amato M, et al. Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett’s esophagus, and gastroesophageal reflux. J Natl Cancer Inst 2013;105:1711–1718. 28. Su Z, Gay LJ, Strange A, et al. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett’s esophagus. Nat Genet 2012;44:1131–1136. 29. Ormestad M, Astorga J, Landgren H, et al. Foxf1 and Foxf2 control murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production. Development 2006;133:833–843. 30. Dura P, van Veen EM, Salomon J, et al. Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk. Int J Cancer 2013;133:1751–1755. 31. Levine DM, Ek WE, Zhang R, et al. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett’s esophagus. Nat Genet 2013; 45:1487–1493.
18. Chak A, Faulx A, Kinnard M, et al. Identification of Barrett’s esophagus in relatives by endoscopic screening. Am J Gastroenterol 2004;99:2107–2114.
32. Verbeek RE, Spittuler LF, Peute A, et al. Familial clustering of Barrett’s esophagus and esophageal adenocarcinoma in a European cohort. Clin Gastroenterol Hepatol 2014. Epub ahead of print.
19. Pohl H, Wrobel K, Bojarski C, et al. Risk factors in the development of esophageal adenocarcinoma. Am J Gastroenterol 2013;108:200–207.
33. Rubenstein JH, Morgenstern H, Appelman H, et al. Prediction of Barrett’s esophagus among men. Am J Gastroenterol 2013; 108:353–362.
20. Smith KJ, O’Brien SM, Smithers BM, et al. Interactions among smoking, obesity, and symptoms of acid reflux in Barrett’s esophagus. Cancer Epidemiol Biomarkers Prev 2005;14: 2481–2486. 21. Lagergren J, Bergstrom R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:825–831.
34. Thrift AP, Kendall BJ, Pandeya N, et al. A clinical risk prediction model for Barrett esophagus. Cancer Prev Res (Phila) 2012; 5:1115–1123.
22. Kramer JR, Fischbach LA, Richardson P, et al. Waist-to-hip ratio, but not body mass index, is associated with an increased risk of Barrett’s esophagus in white men. Clin Gastroenterol Hepatol 2013;11:373–381.e1.
35. Thrift AP, Kendall BJ, Pandeya N, et al. A model to determine absolute risk for esophageal adenocarcinoma. Clin Gastroenterol Hepatol 2013;11:138–144.e2.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.03.008
B
Familial Aggregation of Gastroesophageal Reflux Disease, Barrett’s Esophagus, and Esophageal Adenocarcinoma There is evidence implicating genetic factors, even in the development of gastroesophageal reflux disease (GERD). Two studies, one by Romero et al4 and one by Trudgill et al,5 have shown a significantly increased prevalence of GERD among family members of patients with BE and EAC. The higher concordance of reflux symptoms found in monozygotic twins compared with dizygotic twins with an estimated polygenic heritability of 30% to 40% further strengthens a genetic hypothesis.6–8 However, molecular studies that identify genetic factors to explain familial GERD are awaited. Familial aggregation is the first evidence/recognition of the genetic basis of disease. Numerous case reports starting in the 1970s documented familial clusters of BE and EAC.7,9–12 The prevalence of verified BE within these families was well over 20%, compared with a less than 3% prevalence in the general population.13 The next step in the evidence chain was a hospital-based, case-control study in which we showed aggregation of BE and associated cancers in Caucasian families.14 This phenomenon was termed familial Barrett’s esophagus.15 Subsequently, the prevalence of familial BE in patients with these diseases was estimated to be 6% to 7.3%.16,17 In a follow-up prospective study, we showed that endoscopic screening of relatives of familial BE probands identified new BE
cases. This finding added credence to the familial clustering hypothesis, and also provided practical implications for high-risk screening.18 Familial aggregation must be interpreted cautiously. Aggregation of BE and EAC could be owing to common environmental exposures in families, such as smoking,19,20 diet, a genetic or inherited susceptibility to risk factors such as obesity or GERD,21–23 a genetic susceptibility to the development of metaplastic or neoplastic esophageal epithelium, or a combination of these effects. BE and EAC occur at a younger age in affected members of multiply affected BE families.24,25 Appearance of disease in younger individuals, which normally would not manifest until older ages in sporadic cases, also is supportive of the genetic hypothesis. Based on previous studies,14,24 we postulated that, similar to other metaplastic and neoplastic diseases, the development of Barrett’s epithelium and subsequent adenocarcinomas is caused by complex pathways involving inherited germline mutations and environmentally induced acquired somatic mutations. A study of inheritance patterns in 70 BE families by The Familial Barrett Esophagus Consortium suggested that inheritance of familial BE is autosomal dominant.24 Furthermore, our segregation analysis of 881 familial BE pedigrees provided reasonable epidemiologic evidence in support of the inheritance of one or more rare, autosomal-dominant susceptibility alleles.15 These findings suggest Mendelian inheritance, not necessarily monogenic, with markedly reduced penetrance as a result of environmental factors.
Findings From Genetic Linkage and Genome-Wide Association Studies More recent genetic linkage studies and genome-wide association studies (GWAS) have provided direct evidence of a genetic predisposition. A linkage study followed by a fine mapping association study of familial BE identified association with single nucleotide polymorphisms (SNPs) in the MSR1 (8p), ASCC1 (10q), and CTHRC1 (8q) genes,26 which are involved in macrophage function and inflammatory pathways. A GWAS by the Barrett’s and Esophageal Adenocarcinoma Consortium showed that both BE and EAC are influenced by multiple germline genetic variants of small effect. By using genome-wide genotype data on unrelated cases and controls, as opposed to traditional twin studies of heritability, Barrett’s and Esophageal Adenocarcinoma Consortium investigators measured the array heritability for BE and EAC to be 35% and 25%, respectively.27 They also found a significant polygenic overlap and a strong genetic correlation between BE and EAC, suggesting substantial shared genetic architecture between BE and EAC. Clinical Gastroenterology and Hepatology 2014;-:-–-
2
Sun et al
A large GWAS study, the first of its kind, using unrelated BE cases and controls, identified 2 SNPs on 2 chromosomes, namely 6p21 and 16q24, to be associated significantly with risk of BE.28 The 16q24 is of particular interest because its closest protein coding gene, termed FOXF1, serves as a transcription factor in the hedgehog signaling pathway. FOXF1 has an important role in the development of the foregut during organogenesis.29 It also has been shown that certain FOXF1 variants that are responsible for increased BE risk also increase the risk of EAC in Caucasians.30 A recent unrelated case-control GWAS that looked at EACs as well as BE, in addition to confirming the previous associations with FOXF1 and HLA loci, identified new susceptibility loci on chromosomes 19p, 9q, and 3p, in the region of genes associated with oncogenic activity and transcription factors in esophageal specification and esophageal development.31 The finding that the previously identified Barrett’s esophagus association locus also has a role in EAC risk suggests that much of the genetic basis for EAC lies in the development of BE. These associations have provided direct evidence that BE has a genetic component, and imply that we may be close to finding important pathways in the development of BE and EAC. Future linkage and GWAS studies that concentrate on familial Barrett’s esophagus in multiplex Barrett’s families may identify new genetic susceptibility variants because of the increased genetic components in such samples. The study by Verbeek et al32 in this issue adds to the growing evidence for the familiality of BE and EAC. They studied a large European cohort of 838 index patients with BE or EAC and their relatives by administering questionnaires. A diagnosis of familial BE was made after histologic confirmation of intestinal metaplasia in 1 or more first- or second-degree relatives of the index patient. The prevalence of familial BE was found to be 7%, consistent with previous results in US populations,16,17 They also found familial BE cases to have a significantly younger age of onset of heartburn and EAC diagnosis than nonfamilial cases, and reflux symptoms were reported more frequently among first-degree relatives of familial BE cases than those of nonfamilial BE cases—not only strengthening the earlier reports of younger affection status in familial BE,24,25 but also consistently supporting the genetic hypothesis of GERD, BE, and EAC.
Inferences and Conclusions Advances have been made over the past decade in our understanding of genetic and environmental factors associated with GERD, BE, and EAC, which can guide the development of risk prediction models in populations and families. Genetic susceptibility variants of BE identified in epidemiologic studies need to be validated further by functional analysis, and more susceptibility genes probably remain to be discovered by more powerful
Clinical Gastroenterology and Hepatology Vol.
-,
No.
-
approaches such as by studying more genetically informative samples. The complexity of familial BE suggests we need further studies to determine the genetic causal variants and explain the mechanisms by which these variants control the development of BE and EAC. There are several regression models developed to predict BE and EAC risk in case-control populations with moderate prediction accuracy.33–35 New screening and prediction tools with better performance to predict risk, especially in BE families, are needed, however, unless based on known causal mechanisms, a model cannot be expected to apply to populations other than the one in which it was estimated. The discovery of SNPs at major loci of gene transcription that are known to play a role in metaplastic and dysplastic changes show that we are closer than ever before to finding the genes associated with BE and EAC. Assessing individual genetic susceptibility may help target high-risk patients for endoscopic screening programs rather than using a cost-ineffective, population-wide approach. XIANGQING SUN, PhD Division of Epidemiology and Biostatistics Case Western Reserve University Cleveland, Ohio APOORVA KRISHNA CHANDAR, MBBS, MA, MPH Division of Gastroenterology and Hepatology Case Western Reserve University Cleveland, Ohio ROBERT ELSTON, PhD Division of Epidemiology and Biostatistics Case Western Reserve University Cleveland, Ohio AMITABH CHAK, MD Division of Gastroenterology and Hepatology Case Western Reserve University Cleveland, Ohio
References 1. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 2014;64:9–29. 2. Simard EP, Ward EM, Siegel R, et al. Cancers with increasing incidence trends in the United States: 1999 through 2008. CA Cancer J Clin 2012;62:118–128. 3. Thrift AP, Whiteman DC. The incidence of esophageal adenocarcinoma continues to rise: analysis of period and birth cohort effects on recent trends. Ann Oncol 2012;23:3155–3162. 4. Romero Y, Cameron AJ, Locke GR 3rd, et al. Familial aggregation of gastroesophageal reflux in patients with Barrett’s esophagus and esophageal adenocarcinoma. Gastroenterology 1997;113:1449–1456. 5. Trudgill NJ, Kapur KC, Riley SA. Familial clustering of reflux symptoms. Am J Gastroenterol 1999;94:1172–1178. 6. Mohammed I, Cherkas LF, Riley SA, et al. Genetic influences in gastro-oesophageal reflux disease: a twin study. Gut 2003; 52:1085–1089.
-
2014
7. Gelfand MD. Barrett esophagus in sexagenarian identical twins. J Clin Gastroenterol 1983;5:251–253. 8. Cameron AJ, Lagergren J, Henriksson C, et al. Gastroesophageal reflux disease in monozygotic and dizygotic twins. Gastroenterology 2002;122:55–59. 9. Everhart CW, Holtzapple PG, Humphries TJ. Occurrence of Barrett’s esophagus in three members of the same family: first report of familial incidence. Gastroenterology 1978;74:A1032. 10. Prior A, Whorwell PJ. Familial Barrett’s oesophagus? Hepatogastroenterology 1986;33:86–87. 11. Eng C, Spechler SJ, Ruben R, et al. Familial Barrett esophagus and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol Biomarkers Prev 1993;2:397–399. 12. Poynton AR, Walsh TN, O’Sullivan G, et al. Carcinoma arising in familial Barrett’s esophagus. Am J Gastroenterol 1996; 91:1855–1856. 13. Ronkainen J, Aro P, Storskrubb T, et al. Prevalence of Barrett’s esophagus in the general population: an endoscopic study. Gastroenterology 2005;129:1825–1831. 14. Chak A, Lee T, Kinnard MF, et al. Familial aggregation of Barrett’s oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults. Gut 2002;51:323–328. 15. Sun X, Elston R, Barnholtz-Sloan J, et al. A segregation analysis of Barrett’s esophagus and associated adenocarcinomas. Cancer Epidemiol Biomarkers Prev 2010;19:666–674. 16. Chak A, Ochs-Balcom H, Falk G, et al. Familiality in Barrett’s esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction. Cancer Epidemiol Biomarkers Prev 2006;15:1668–1673. 17. Ash S, Vaccaro BJ, Dabney MK, et al. Comparison of endoscopic and clinical characteristics of patients with familial and sporadic Barrett’s esophagus. Dig Dis Sci 2011;56:1702–1706.
Editorial
3
23. Singh S, Sharma AN, Murad MH, et al. Central adiposity is associated with increased risk of esophageal inflammation, metaplasia, and adenocarcinoma: a systematic review and metaanalysis. Clin Gastroenterol Hepatol 2013;11:1399–1412.e7. 24. Drovdlic CM, Goddard KA, Chak A, et al. Demographic and phenotypic features of 70 families segregating Barrett’s oesophagus and oesophageal adenocarcinoma. J Med Genet 2003;40:651–656. 25. Chak A, Chen Y, Vengoechea J, et al. Variation in age at cancer diagnosis in familial versus nonfamilial Barrett’s esophagus. Cancer Epidemiol Biomarkers Prev 2012;21:376–383. 26. Orloff M, Peterson C, He X, et al. Germline mutations in MSR1, ASCC1, and CTHRC1 in patients with Barrett esophagus and esophageal adenocarcinoma. JAMA 2011;306:410–419. 27. Ek WE, Levine DM, D’Amato M, et al. Germline genetic contributions to risk for esophageal adenocarcinoma, Barrett’s esophagus, and gastroesophageal reflux. J Natl Cancer Inst 2013;105:1711–1718. 28. Su Z, Gay LJ, Strange A, et al. Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett’s esophagus. Nat Genet 2012;44:1131–1136. 29. Ormestad M, Astorga J, Landgren H, et al. Foxf1 and Foxf2 control murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production. Development 2006;133:833–843. 30. Dura P, van Veen EM, Salomon J, et al. Barrett associated MHC and FOXF1 variants also increase esophageal carcinoma risk. Int J Cancer 2013;133:1751–1755. 31. Levine DM, Ek WE, Zhang R, et al. A genome-wide association study identifies new susceptibility loci for esophageal adenocarcinoma and Barrett’s esophagus. Nat Genet 2013; 45:1487–1493.
18. Chak A, Faulx A, Kinnard M, et al. Identification of Barrett’s esophagus in relatives by endoscopic screening. Am J Gastroenterol 2004;99:2107–2114.
32. Verbeek RE, Spittuler LF, Peute A, et al. Familial clustering of Barrett’s esophagus and esophageal adenocarcinoma in a European cohort. Clin Gastroenterol Hepatol 2014. Epub ahead of print.
19. Pohl H, Wrobel K, Bojarski C, et al. Risk factors in the development of esophageal adenocarcinoma. Am J Gastroenterol 2013;108:200–207.
33. Rubenstein JH, Morgenstern H, Appelman H, et al. Prediction of Barrett’s esophagus among men. Am J Gastroenterol 2013; 108:353–362.
20. Smith KJ, O’Brien SM, Smithers BM, et al. Interactions among smoking, obesity, and symptoms of acid reflux in Barrett’s esophagus. Cancer Epidemiol Biomarkers Prev 2005;14: 2481–2486. 21. Lagergren J, Bergstrom R, Lindgren A, et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999;340:825–831.
34. Thrift AP, Kendall BJ, Pandeya N, et al. A clinical risk prediction model for Barrett esophagus. Cancer Prev Res (Phila) 2012; 5:1115–1123.
22. Kramer JR, Fischbach LA, Richardson P, et al. Waist-to-hip ratio, but not body mass index, is associated with an increased risk of Barrett’s esophagus in white men. Clin Gastroenterol Hepatol 2013;11:373–381.e1.
35. Thrift AP, Kendall BJ, Pandeya N, et al. A model to determine absolute risk for esophageal adenocarcinoma. Clin Gastroenterol Hepatol 2013;11:138–144.e2.
Conflicts of interest The authors disclose no conflicts. http://dx.doi.org/10.1016/j.cgh.2014.03.008
