Risk factors, DNA damage, and disease progression in Barrett's esophagus.

Esophageal adenocarcinoma develops on a background of Barrett's esophagus. A number of risk factors have been linked to both conditions, including gastroesophageal reflux and smoking. However, the molecular mechanisms by which these factors influence disease progression remain unclear. One possibility is that risk factors generate promutagenic DNA damage in the esophagus. The comet assay was used to measure DNA damage in esophageal (Barrett's and squamous) and gastric mucosa of Barrett's patients with (n = 24) or without (n = 50) associated adenocarcinoma or high-grade dysplasia in comparison with control patients (squamous mucosa) without Barrett's esophagus (n = 64). Patients completed a questionnaire detailing exposure to some of the known risk factors for Barrett's esophagus and adenocarcinoma. In Barrett's esophagus patients, DNA damage was higher in Barrett's mucosa compared with normal esophageal and gastric mucosa (P < 0.001). In addition, the highest quartile of DNA damage in Barrett's mucosa was associated with an increased risk (odds ratio, 9.4; 95% confidence interval, 1.1-83.4; P = 0.044) of developing adenocarcinoma or high-grade dysplasia compared with DNA damage levels in the lowest quartile. Smoking was associated with higher DNA damage in squamous epithelium in all patient groups (P < 0.01) and in Barrett's mucosa (P < 0.05) in Barrett's esophagus patients only. In controls only, current reflux was associated with higher DNA damage, whereas anti-inflammatory drug use resulted in lower levels. Collectively, these data imply a genotoxic insult to the premalignant Barrett's mucosa that may explain the genetic instability in this tissue and the progression to adenocarcinoma. There is an indication for a role for smoking in inducing DNA damage in esophageal mucosa but an understanding of the role of reflux requires further investigation.     

p53 in esophageal adenocarcinoma: a critical reassessment of mutation frequency and identification of 72Arg as the dominant allele

p53 alterations have been implicated in the progression of Barrett's esophagus to esophageal adenocarcinoma. However, the wide range of reported p53 alteration frequencies in esophageal adenocarcinoma makes using p53 as a marker of malignant transformation of Barrett's esophagus problematic. To determine the utility of p53 in Barrett's esophagus monitoring, the frequency of p53 alteration was critically reassessed using esophagectomy specimens of 40 cases of esophageal adenocarcinoma, including 10 with Barrett's esophagus and high-grade dysplasia, 8 with low-grade dysplasia and 7 with no dysplasia. DNA was extracted from tumor cells isolated by laser capture microdissection to maximize the assay sensitivity and mutations in exons 4-8 of p53 were determined by PCR direct sequencing. Mutations in p53 were identified in 75% (30/40) of the esophageal adenocarcinoma. p53 protein overexpression, detected by immunohistochemistry, was found in 58% (23/40) of the esophageal adenocarcinoma, 60% (6/10) of Barrett's esophagus with high-grade dysplasia, 12% (1/8) of Barrett's esophagus with low-grade dysplasia, and 0% of Barrett's esophagus without dysplasia. In addition to the mutations, a predominance of the 72Arg allele (89% homozygous) was found over the 72Pro allele in this series. p53 mutation frequency in this study was higher than reported in most of the literature and DNA sequencing detected more p53 alterations than immunohistochemical staining. However, p53 appeared to be a late marker in the neoplastic transformation, and no p53 change was found in approximately 25% of the adenocarcinoma. We concluded that p53 is insufficient as a single marker for Barrett's esophagus monitoring but may be useful as part of a panel due to its high specificity.     

Analysis of Ki-67, p53 and Bcl-2 expression in the dysplasia-carcinoma sequence of Barrett's esophagus.

The grading of dysplasia in Barrett's esophagus has prognostic importance, however observer variation limits the reliability of simple histological analysis alone. We investigated Ki-67, p53 and Bcl-2 expression in Barrett's esophagus, in the sequence from Barrett's low-grade dysplasia to high-grade dysplasia and infiltrating adenocarcinoma. Forty-four esophagectomy specimens were utilized: 39 specimens with esophageal dysplasia and adenocarcinoma and 5 specimens with esophageal dysplasia only. This gave 83 sections (2 sections for specimens with dyplasia and carcinoma) examined from 44 patients. The sections were examined for Ki-67, p53 and Bcl-2 reactivity by immunohistochemistry. Low-grade dysplasia was present in 14 sections, high-grade dysplasia in 30 sections and carcinoma in 39 sections. Ki-67 expression occurred in 2 out of 14 (14%) sections with low-grade dysplasia, in 22 out of 30 (73%) sections with high-grade dysplasia and in 34 out of 39 (87%) sections with carcinoma (p<0.001). p53 protein expression was found in 1 of 14 (7%) sections with low-grade dysplasia, in 18 of 30 (60%) sections with high-grade dysplasia and in 33 of 39 (85%) sections with carcinoma (p<0.001). Expression of Bcl-2 was found in 11 of 14 (84%) sections with low-grade dysplasia but immunoreactivity was not seen in any section with high-grade dysplasia or Barrett's carcinoma. Our results indicate that overexpression of Ki-67, Bcl-2 protein and p53 mutations can be identified as early events during neoplastic progression in Barrett's esophagus. These data support the hypothesis that, in the progression of Barrett's metaplasia to adenocarcinoma, the balance of proliferation/apoptosis plays an important role.     

Genomic alterations in malignant transformation of Barrett's esophagus

The incidence of adenocarcinoma in Barrett's esophagus has been increasing rapidly over the past decades. Neoplastic progression is characterized by three well-defined premalignant stages: metaplasia, low-grade dysplasia, and high-grade dysplasia. A genome-wide overview, based on comparative genomic hybridization, was performed, evaluating 30 Barrett's adenocarcinomas and 25 adjacent precursors, i.e., 6 metaplasias, 9 low-grade dysplasias, and 10 high-grade dysplasias. The frequency of losses and gains significantly increased in the subsequent stages of malignant transformation. Losses of 5q21-q23, 9p21, 17p12-13.1, 18q21, and Y were revealed in low-grade dysplasias. This was followed by loss of 7q33-q35 and gains of 7p12-p15, 7q21-q22, and 17q21 in high-grade dysplasias along with high-level amplification (HLA) of 7q21 and 17q21. In the invasive cancers, additional losses of 3p14-p21, 4p, 4q, 8p21, 13q14-q31, 14q24.3-q31, 16q21-q22, and 22q as well as gains of 3q25-q27, 8q23-24.1, 12p11.2-12, 15q22-q24, and 20q11.2-q13.1 were distinguished along with HLAs of 8p12-p22 and 20q11.2-q13.1. Approximately one-third of the alterations in the dysplasias were also found in the adjacent adenocarcinomas, illustrating that multiple clonal lineages can be present in Barrett's esophagus. Novel findings include loss on 7q, gain on 12p, and the observation of several HLAs in high-grade dysplasias. Furthermore, loss of 7q33-q35 was found to represent a significant distinction between low-grade and high-grade dysplasia (P = 0.01), whereas loss of 16q21-q22 and gain of 20q11.2-q13.1 were disclosed to significantly discriminate between high-grade dysplasia and adenocarcinoma (P = 0.02 and P = 0.03, respectively). This inventory of genetic aberrations increases our understanding of malignant transformation in Barrett's esophagus and might provide useful biomarkers for disease progression.     

Progression of Barrett's metaplasia to adenocarcinoma is associated with the suppression of the transcriptional programs of epidermal differentiation

We did expressional profiling on 24 paired samples of normal esophageal epithelium, Barrett's metaplasia, and esophageal adenocarcinomas. Matching tissue samples representing the three different histologic types were obtained from each patient undergoing esophagectomy for adenocarcinoma. Our analysis compared the molecular changes accompanying the transformation of normal squamous epithelium with Barrett's esophagus and adenocarcinoma in individual patients rather than in a random cohort. We tested the hypothesis that expressional profiling may reveal gene sets that can be used as molecular markers of progression from normal esophageal epithelium to Barrett's esophagus and adenocarcinoma. Expressional profiling was done using U133A GeneChip (Affymetrix), which represent approximately two thirds of the human genome. The final selection of 214 genes permitted the discrimination of differential gene expression of normal esophageal squamous epithelium, Barrett's esophagus, and adenocarcinoma using two-dimensional hierarchical clustering of selected genes. These data indicate that transformation of Barrett's esophagus to adenocarcinoma is associated with suppression of the genes involved in epidermal differentiation, including genes in 1q21 loci and corresponding to the epidermal differentiation complex. Correlation analysis of genes concordantly expressed in Barrett's esophagus and adenocarcinoma revealed 21 genes that represent potential genetic markers of disease progression and pharmacologic targets for treatment intervention. PCR analysis of genes selected based on DNA array experiments revealed that estimation of the ratios of GATA6 to SPRR3 allows discrimination among normal esophageal epithelium, Barrett's dysplasia, and adenocarcinoma.     

Persistent clonal areas and clonal expansion in Barrett's esophagus.

Three patients with Barrett's esophagus who had cytogenetic abnormalities detected in their metaplastic epithelium developed high-grade dysplasia or adenocarcinoma during prospective surveillance over a period of 1.5 to 6 years. In the 3 cases, cytogenetic abnormalities that were associated with the most advanced histological lesions were present in samples obtained 11, 25, and 48 months prior to the diagnosis of high-grade dysplasia or carcinoma. In a fourth patient, marker chromosomes found in a Barrett's adenocarcinoma were also present in an esophageal region spatially removed from the tumor. In all four patients, clonal cytogenetic abnormalities were present in samples obtained at widespread locations in the Barrett's segment. These observations suggest that in some patients with Barrett's esophagus clonal proliferations arise in regions of benign histology and spread to involve large areas of Barrett's mucosa. These clones persisted when the disease progressed to high-grade dysplasia or adenocarcinoma.     

Management of Barrett's esophagus

Barrett's esophagus represents replacement of normal distal esophageal squamous epithelium with specialized columnar epithelium containing goblet cells. Typically arising in the setting of chronic gastroesophageal reflux disease, the presence of Barrett's esophagus carries a 50- to 100-fold increased risk of developing esophageal cancer. Risk factors include male sex, smoking history, obesity, Caucasian ethnicity, age > 50 and > 5-year history of reflux symptoms. Aggressive medical or surgical antireflux therapy may ameliorate symptoms, but have not yet been proven to affect the risk of developing esophageal adenocarcinoma in randomized trials. Although dysplasia is an imperfect biomarker for the development of subsequent malignancy, random sampling of esophageal tissue for dysplasia remains the clinical standard. There have been no studies to establish that endoscopic screening/surveillance programs decrease the rates of death from cancer. Fit patients with Barrett's esophagus and high-grade dysplasia should undergo esophagectomy to prevent the risk of developing esophageal adenocarcinoma. For non-operative candidates, endoscopic ablative approaches may represent a reasonable therapeutic alternative.     

A comparative cytopathologic and histologic study of atypia, dysplasia, and adenocarcinoma in Barrett's esophagus.

As a potentially premalignant condition, Barrett's esophagus has stimulated controversy over the need for surveillance of glandular dysplasia and early carcinoma. This prompted the authors to review their experience with endoscopic cytologic brushings and biopsies from patients with Barrett's esophagus. The authors reviewed 65 consecutive specimens from 42 patients with Barrett's esophagus in which both the concurrently obtained esophageal cytologic brushings and companion biopsy specimens were available. In addition, esophagogastrectomy specimens from 9 nine these patients were reviewed. Cytologic and histologic specimens were assigned to one of four diagnostic categories, based on specifically defined criteria: simple Barrett's esophagus with or without inflammatory atypia; dysplasia; adenocarcinoma; or suspicious for dysplasia or carcinoma. Simple Barrett's esophagus was diagnosed in 38 cytologic brushings and 44 biopsy specimens, dysplasia in 4 brushings and 7 biopsy specimens, and carcinoma in 14 brushings and 10 biopsy specimens. Nine brushings and three biopsy specimens were suspicious. In 13 cases, brushings revealed a higher grade lesion than did histology; in 5 cases, biopsy specimens showed a higher grade lesion. Agreement between the two occurred in 72% (47/65) of all specimens. Accuracy was confirmed in the histologic examinations of the resection specimens. The authors conclude that specific criteria, when consistently applied, allow accurate cytologic diagnoses of epithelial changes in Barrett's esophagus. The use of esophageal brush cytology and biopsy specimens provides two complementary techniques, which detect a greater number of serious lesions than either technique alone.     

Role of Helicobacter pylori cagA(+) strains and specific host immune responses on the development of premalignant and malignant lesions in the gastric cardia.

The incidence rates of gastric cardia and esophageal adenocarcinomas are increasing, but data suggest that carriage of cagA(+) Helicobacter pylori strains may protect against development of Barrett's esophagus and esophageal adenocarcinoma. Our aims were to examine the relationship between pre-malignant and malignant lesions in the gastric cardia and serum antibodies to H. pylori antigens in patients with and without complications of Barrett's esophagus. The prevalence of carditis was 40% in controls compared with 13% in patients with complicated or uncomplicated Barrett's esophagus and cardia adenocarcinoma (p < 0.001). Cardia intestinal metaplasia (IM) and atrophy were present and concordant in 28% of controls but less frequent in patients with Barrett's alone or with dysplasia/adenocarcinoma (0% for each, p < 0.001). Carriage of cagA(+) strains was present in 34% of patients with carditis and significantly associated with increased frequency and severity of cardia inflammation, IM, and atrophy but not with adenocarcinoma. IgA and HspA seropositivity were significantly increased in H. pylori-colonized patients with carditis compared to persons with normal cardia histology (p 相似文献   

Barrett metaplasia: reassessment of treatment and follow-up

PURPOSE OF REVIEW: The incidence of esophageal adenocarcinoma continues to rise in the Western world, with a mean 5-year survival of less than 20%. There has therefore been increasing interest in the precursor lesion, Barrett's esophagus. However, adenocarcinoma will not develop in most patients with Barrett's esophagus. This review summarizes the data on the management of Barrett's esophagus that have been published since January 2003. RECENT FINDINGS: The control of reflux symptoms significantly improves quality of life, and surgical antireflux therapy may gradually cause regression of the Barrett segment compared with proton pump inhibitor therapy. The data substantiate the claim that the cancer risk in Barrett esophagus is lower than had hitherto been suggested. The risk factors for progression include increasing age and length of segment, macroscopic inflammatory changes, loss of heterozygosity over several genetic loci, and increased proliferation status. The extent of high-grade dysplasia may not accurately predict cancer development, and continued surveillance, rather than intervention, for such patients may decrease the chances of curative treatment. Long-term follow-up data are beginning to accumulate for nonsurgical treatment strategies. Chemoprevention trials are under way to evaluate the role of acid suppression and nonsteroidal anti-inflammatory drugs and their derivatives. SUMMARY: At this time, endoscopic surveillance and surgical management remain the mainstay, but continued research efforts should enable risk stratification and cancer prevention in the future.     

Estrogen receptor-beta is expressed in Barrett's metaplasia and associated adenocarcinoma of the esophagus

Estrogen receptor-beta (ER-B) has been identified in benign and malignant tissues of a variety of human organs including the colon. In breast carcinoma, ER-B was found to be a significant predictor of response to adjuvant hormonal therapy with tamoxifen. The aim of the present study was to determine whether esophageal adenocarcinoma, and its precursosr, Barrett's metaplasia, express ER-B. Sections of formalin-fixed and paraffin-embedded tissue from 31 esophagectomy specimens were immunostained for ER-B using the immunoperoxidase technique, and the percent of positive cells in areas of Barrett's metaplasia negative for dysplasia (ND), low-grade dysplasia (LGD), high-grade dysplasia (HGD) and adecocarcinoma, (CA) were recorded. Nuclear ER-B staining in >50% of the cells was seen in all 23 CA (100%), 10 out of 11 (91%) HGD, 8 out of 11 (83%) LGD and in 10 of 15 (66.6%) ND. It is concluded that all adenocarcinomas of the esophagus and most precursor lesions, Barrett's Metaplasia (BM) with or without dysplasia, express ER-B in a significantly high percentage of the cells. These findings raise the possibility that esophageal adenocarcinomas may benefit from treatment and/or chemoprevention with antiestrogens, such as tamoxifen.     

Effect of acid suppression on molecular predictors for esophageal cancer.

BACKGROUND: Gastroesophageal reflux disease is a risk factor for the development of Barrett's esophagus and esophageal adenocarcinoma. The effect of antireflux therapy on the incidence of esophageal adenocarcinoma is unknown. Acid exposure in vitro induces hyperproliferation via a cyclooxygenase-2 (COX-2) dependent mechanism. Epidemiologic and animal studies suggest that COX inhibitors decrease the incidence of esophageal adenocarcinoma.Aim: To study the differential effect of complete compared with incomplete acid suppression on proliferation, apoptosis, and COX-2.Patients and METHODS: Fifty-one patients with Barrett's esophagus who underwent pH monitoring were divided into two groups according to their DeMeester score: 32 acid-suppressed patients (group 1) and 19 patients with abnormally high acid exposure (group 2). Slides from biopsies taken 3 months before and 4 and 12 months after pH monitoring were stained for Mcm2, COX-2, c-myc, and cleaved caspase-3 (marker of apoptosis).RESULTS: There was no evidence of a difference between the two groups in terms of age, gender ratio, medication, dysplasia status, and the expression levels of any marker before pH monitoring. In group 1, Mcm2 expression decreased in the luminal surface and throughout the tissue 12 months after monitoring when compared with the two previous time points (P < 0.05). The levels of COX-2 increased overtime (P < 0.01 in group 1, not significant in group 2). There was no correlation between Mcm2 and COX-2 expression. Acid suppression had no effect on c-myc or apoptosis.CONCLUSION: Long-term acid suppression reduces proliferation in Barrett's esophagus samples but has no advantageous effect on c-myc, apoptosis, or COX-2.     

Activation of c-Ki-ras in human gastrointestinal dysplasias determined by direct sequencing of polymerase chain reaction products

Activation of c-Ki-ras by point mutation within exon 1 was studied in 33 specimens of dysplastic gastrointestinal lesions or of cancers presumed to arise from dysplasia. Samples were obtained from patients with underlying ulcerative colitis or Barrett's esophagus, two diseases associated with dysplasia and increased rates of colonic or esophageal adenocarcinoma, respectively. Genomic DNA was amplified using primers bounding this exon in the polymerase chain reaction. Polymerase chain reaction products were analyzed by direct dideoxy sequencing. Three point mutations in codon 13 of c-Ki-ras were found, all in colonic specimens (two high-grade dysplasias and one adenocarcinoma arising in ulcerative colitis). No point mutations were observed in the second exon of c-Ki-ras or in and around codons 12, 13, and 61 of c-N-ras and C-Ha-ras in a partial sampling of the specimens. These data indicate that ras family protooncogene activation is an uncommon event at this level of malignant progression in these disease states. Carcinogenesis in ulcerative colitis and Barrett's esophagus may proceed via different pathways than in sporadic colon cancer, perhaps involving loss or inactivation of suppressor genes.     

Barretts carcinoma in a 25-year-old man with point mutation of the p53 tumor suppressor gene

Barrett's esophagus is a recognized risk factor for adenocarcinoma of the esophagus. Dysplasia in Barrett's epithelium is considered a precursor to malignancy. Several tumor suppressor genes, including p53, have recently been implicated in the pathogenesis of esophageal adenocarcinoma. However, the interval between the development of Barrett's esophagus, dysplasia, and frank malignancy is usually very long. A case of adenocarcinoma of the esophagus arising from Barrett's esophagus in a 25-year-old man is discussed. Point mutation in exon 8 of p53 was discovered in this patient's tumor and surrounding dysplastic Barrett's mucosa. To our knowledge, this is the youngest reported case of Barrett's-associated esophageal adenocarcinoma in the medical literature. It suggests that acquired somatic mutations in tumor suppressor genes may occur early in life and that these mutations may contribute to the development of dysplasia and cancer in Barrett's esophagus.     

周期蛋白B1和D1在重度反流性食管炎、Barrett食管和食管腺癌中的表达及相关性研究

 目的　探讨周期蛋白（Cyclin）B1及D1在Barrett食管、Barrett食管合并不典型增生（DY）和食管腺癌中表达的临床意义。方法　应用免疫组织化学SP法测定68例患者食管组织标本Cyclin B1和Cyclin D1,其中重度反流性食管炎（RE）25例,Barrett食管（BE）35例,其中8例DY,8例食管腺癌（EA）,另取10例正常食管黏膜组织作为对照。结果　Cyclin B1 和Cyclin D1在 BE、DY、EA组检测样本中均有高表达,而在正常对照组及RE组黏膜组织中仅有少量表达,差异有统计学意义（P＜0.01）,且Cyclin D1表达从肠化生-不典型增生-腺癌组织依次增高（分别为50.04、 67.94、74.31）,差异有统计学意义（P＜0.01）。结论　Cyclin B1和 cyclin D1可以作为肿瘤进展标志物来评估Barrett食管患者进展为腺癌的危险性,并可能是食管腺癌发生过程中的早期事件。     

Barrett's mucosa in conjunction with squamous carcinoma of the esophagus

Fifty esophagectomies (32 specimens with squamous cell carcinoma and 18 with adenocarcinoma) were reviewed for the presence of Barrett's mucosa. The whole resected specimens were cut, and a total of 1677 blocks (measuring up to 4.0 x 0.5 cm) were obtained. In resections with squamous cell carcinoma, a mean of 33.6 sections (range, 16 to 55 sections) were excised, and in those with adenocarcinomas, a mean of 33.4 sections (range, ten to 60 sections) were cut. Barrett's mucosa (without or with dysplasia) was present in all 18 specimens with an adenocarcinoma (100%) and in 13 of the 32 specimens (40.6%) with squamous cell carcinoma. In ten of the 13 specimens with squamous cell carcinoma, adjacent areas with high-grade squamous cell dysplasia were found. The squamous cell carcinoma and/or the adjacent squamous cell dysplasia were found separated from the Barrett's mucosa by normal squamous epithelium, supporting the view that these two lesions are not related to one another. Early clinical and experimental data showed that squamous cell dysplasia antedated the development of squamous cell carcinoma in that organ. One possible suggestive of these findings is that the detection of a Barrett's esophagus (without or with dysplasia) should prompt the endoscopist also to examine carefully the rest of the esophagus to exclude mucosal alterations possibly connected with squamous cell carcinogenesis in that organ.     

No association between hOGG1, XRCC1, and XPD polymorphisms and risk of reflux esophagitis, Barrett's esophagus, or esophageal adenocarcinoma: results from the factors influencing the Barrett's adenocarcinoma relationship case-control study.

Reflux of gastric contents can lead to development of reflux esophagitis and Barrett's esophagus. Barrett's esophagus is a risk factor for esophageal adenocarcinoma. Damage to DNA may lead to carcinogenesis but is repaired through activation of pathways involving polymorphic enzymes, including human 8-oxoguanine glycosylase 1 (hOGG1), X-ray repair cross-complementing 1 (XRCC1), and xeroderma pigmentosum group D (XPD). Of the single nucleotide polymorphisms identified in these genes, hOGG1 Ser 326 Cys, XRCC1 Arg 399 Gln, and XPD Lys 751 Gln are particularly common in Caucasians and have been associated with lower DNA repair capacity. Small studies have reported associations with XPD Lys 751 Gln and esophageal adenocarcinoma. XRCC1 Arg 399 Gln has been linked to Barrett's esophagus and reflux esophagitis. In a population-based case-control study, we examined associations of the hOGG1 Ser 326 Cys, XRCC1 Arg 399 Gln, and XPD Lys 751 Gln polymorphisms with risk of esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barrett's esophagus (n = 212), reflux esophagitis (n = 230), and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. There were no statistically significant associations between these polymorphisms and risk of esophageal adenocarcinoma, Barrett's esophagus, or reflux esophagitis.     

Cyclooxygenase-2 and inducible nitric oxide synthase gene polymorphisms and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma.

The incidence of esophageal adenocarcinoma has increased in recent years, and Barrett's esophagus is a recognized risk factor. Gastroesophageal reflux of acid and/or bile is linked to these conditions and to reflux esophagitis. Inflammatory disorders can lead to carcinogenesis through activation of "prosurvival genes," including cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Increased expression of these enzymes has been found in esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Polymorphic variants in COX-2 and iNOS genes may be modifiers of risk of these conditions. In a population-based case-control study, we examined associations of the COX-2 8473 T>C and iNOS Ser(608) Leu (C>T) polymorphisms with risk of esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barrett's esophagus (n = 212), and reflux esophagitis (n = 230) and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. The presence of at least one COX-2 8473 C allele was associated with a significantly increased risk of esophageal adenocarcinoma (adjusted odds ratio, 1.58; 95% confidence interval, 1.04-2.40). There was no significant association between this polymorphism and risk of Barrett's esophagus or reflux esophagitis or between the iNOS Ser 608 Leu polymorphism and risk of these esophageal conditions. Our study suggests that the COX-2 8473 C allele is a potential genetic marker for susceptibility to esophageal adenocarcinoma.     

Familiality in Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction.

BACKGROUND AND AIM: The familial aggregation of Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction, jointly termed familial Barrett's esophagus, may represent a complex genetic trait. The aim of this study was to determine the proportion of patients with these diseases who have familial Barrett's esophagus. METHODS: Information on gastroesophageal reflux symptoms, known risk factors for Barrett's esophagus, and family history of Barrett's esophagus and cancers, was collected at six hospitals using a structured questionnaire from probands with either long-segment Barrett's esophagus, adenocarcinoma of the esophagus, or adenocarcinoma of the gastroesophageal junction. Family history of Barrett's esophagus or esophageal cancer in a first- or second-degree relative was determined by reviewing medical records of all relatives reported to be affected. RESULTS: Seventy one of 411 (17.3%) probands reported an affected first- and/or second-degree relative. Upon review of medical records of the reportedly affected relatives, familial Barrett's esophagus was definitively determined in the case of 30 (7.3%) probands comprising 17 of 276 (6.2%) with Barrett's esophagus, 11 of 116 (9.5%) with adenocarcinoma of the esophagus, and 2 of 21 (9.5%) with adenocarcinoma of the gastroesophageal junction. The diagnosis in the relative reported by the proband to be affected was found not to be Barrett's esophagus or adenocarcinoma in 15 (3.6%) cases. The diagnosis could not be determined in 26 (6.3%) cases in which the proband reported an affected relative. There were no significant differences in age of disease onset, gender, race, or gastroesophageal reflux symptoms between definitive familial Barrett's esophagus probands and nonfamilial probands. CONCLUSION: Familial Barrett's esophagus can be confirmed in 7.3% of persons presenting with Barrett's esophagus, adenocarcinoma of the esophagus, or adenocarcinoma of the gastroesophageal junction.