Anderson LA, Watson RP, Murphy SJ, Johnston BT, Comber H, Mc Guigan J, Reynolds JV, Murray LJ. Risk factors for Barrett’s oesophagus and oesophageal adenocarcinoma: Results from the FINBAR study. World J Gastroenterol 2007; 13(10): 1585-1594
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Lesley A Anderson, Centre for Clinical and Population Sciences, Queen’s University, Mulhouse Building, Grosvenor Road, Belfast, BT12 6BJ, Northern Ireland. firstname.lastname@example.org
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Risk factors for Barrett’s oesophagus and oesophageal adenocarcinoma: Results from the FINBAR study
Lesley A Anderson, RG Peter Watson, Seamus J Murphy, Brian T Johnston, Harry Comber, Jim Mc Guigan, John V Reynolds, Liam J Murray
Lesley A Anderson, Liam J Murray, Seamus J Murphy, Centre for Clinical and Population Sciences, Queen’s University, Belfast, Northern Ireland
RG Peter Watson, Brian T Johnston, Jim Mc Guigan, Royal Group of Hospitals, Belfast, Northern Ireland
Harry Comber, National Cancer Registry, Cork, Ireland
John V Reynolds, St. James’s Hospital, Dublin, Ireland
ORCID number: $[AuthorORCIDs]
Author contributions: All authors contributed equally to the work.
Supported by an Ireland-Northern Ireland Co-operation Research Project Grant sponsored by the Northern Ireland Research & Development Office, and the Health Research Board, Ireland. The Ulster Cancer Foundation also funded a PhD student and Post-doctoral fellow to work within the FINBAR study
Correspondence to: Lesley A Anderson, Centre for Clinical and Population Sciences, Queen’s University, Mulhouse Building, Grosvenor Road, Belfast, BT12 6BJ, Northern Ireland. email@example.com
Telephone: +44-28-90635046 Fax: +44-28-90248017
Received: September 11, 2006 Revised: December 5, 2006 Accepted: March 14, 2007 Published online: March 14, 2007
AIM: To investigate risk factors associated with Barrett’s oesophagus and oesophageal adenocarcinoma.
METHODS: This all-Ireland population-based case-control study recruited 224 Barrett’s oesophagus patients, 227 oesophageal adenocarcinoma patients and 260 controls. All participants underwent a structured interview with information obtained about potential lifestyle and environmental risk factors.
RESULTS: Gastro-oesophageal reflux was associated with Barrett’s [OR 12.0 (95% CI 7.64-18.7)] and oesophageal adenocarcinoma [OR 3.48 (95% CI 2.25-5.41)]. Oesophageal adenocarcinoma patients were more likely than controls to be ex- or current smokers [OR 1.72 (95% CI 1.06-2.81) and OR 4.84 (95% CI 2.72-8.61) respectively] and to have a high body mass index [OR 2.69 (95% CI 1.62-4.46)]. No significant associations were observed between these risk factors and Barrett's oesophagus. Fruit but not vegetables were negatively associated with oesophageal adenocarcinoma [OR 0.50 (95% CI 0.30-0.86)].
CONCLUSION: A high body mass index, a diet low in fruit and cigarette smoking may be involved in the progression from Barrett’s oesophagus to oesophageal adenocarcinoma.
Citation: Anderson LA, Watson RP, Murphy SJ, Johnston BT, Comber H, Mc Guigan J, Reynolds JV, Murray LJ. Risk factors for Barrett’s oesophagus and oesophageal adenocarcinoma: Results from the FINBAR study. World J Gastroenterol 2007; 13(10): 1585-1594
Barrett’s oesophagus, a condition of the distal oesophagus in which the normal stratified squamous epithelium is replaced by specialised intestinal metaplasia, is a recognized precursor of oesophageal adenocarcinoma, a cancer that has been increasing in incidence in many Western societies over recent decades[2-6]. It is unknown if all oesophageal adenocarcinomas arise from Barrett’s oesophagus but there is some evidence to suggest that this is the case. In surveillance programs of Barrett’s oesophagus only a minority of patients develop oesophageal adenocarcinoma[8-12] raising the question of what factors are implicated in the development of oesophageal adenocarcinoma from Barrett’s oesophagus.
Several case-control studies have investigated lifestyle factors associated with oesophageal adenocarcinoma[13-19] but few studies of factors associated with Barrett’s oesophagus have been reported[20-22]. Gastro-oesophageal reflux is strongly associated with oesophageal adenocarcinoma[14-17,23,24] and is thought to be the main pre-disposing factor for Barrett’s oesophagus. A small proportion of gastro-oesophageal reflux sufferers develop Barrett’s oesophagus[25-28] and approximately 0.5% of Barrett’s oesophagus patients progress to oesophageal adenocarcinoma each year[8,29-31] indicating that factors apart from gastro-oesophageal reflux are involved in the development of Barrett’s oesophagus and in its progression to oesophageal adenocarcinoma. Several risk factors for oesophageal adenocarcinoma have been established, including a high body mass index (BMI)[15,16,24,32-34], smoking[13,15,19,34,35] and possibly a diet low in fruit and vegetables[16,24,36-38]. Engel et al estimated that these three factors, in combination with gastro-oesophageal reflux, have a population attributable risk for oesophageal adenocarcinoma of 78.7%. However, it is not clear at which stage along the oesophageal inflammation-metaplasia-adenocarcinoma sequence these factors exert their effect. Studies comparing risk factors for Barrett’s oesophagus and oesophageal adenocarcinoma provide the opportunity to examine whether these risk factors are important in the development of Barrett’s oesophagus or in its progression to oesophageal adenocarcinoma. This is crucial to the targeting of preventive efforts aimed at reducing the morbidity and mortality associated with these conditions. We undertook a population-based case-control study of Barrett’s oesophagus and oesophageal adenocarcinoma within Ireland.
MATERIALS AND METHODS
Study details have been described in detail elsewhere. Briefly, the Factors Influencing the Barrett’s Adenocarcinoma Relationship (FINBAR) study recruited three groups of subjects: (1) patients with oesophageal adenocarcinoma, (2) patients with long-segment Barrett’s oesophagus, and (3) normal population controls between March 2002 and December 2004.
Oesophageal adenocarcinoma cases had histological confirmation of adenocarcinoma within the oesophagus. Northern Ireland cases were identified from electronic pathology records from all pathology laboratories within the province. Republic of Ireland cases were identified from the main hospitals involved in the diagnosis and treatment of oesophageal cancer. All available relevant clinical and histological records including endoscopy, surgical and radiological reports were reviewed by LAA, SJM, JM and a pathologist, to confirm that the tumour was located in the oesophagus and to assign tumours into two groups: (1) oesophageal tumours (including tumours encroaching on the esophagogastric junction) and (2) junctional tumours (tumours involving the oesophagus, esophagogastric junction and gastric cardia).
Barrett’s oesophagus patients were eligible for inclusion if ≥ 3 centimetres of typical Barrett’s mucosa were seen at endoscopy and the presence of specialised intestinal metaplasia was confirmed by histological examination of biopsy specimens. Incident and prevalent cases were included and subjects were frequency matched to the age and 5-year sex distribution of oesophageal adenocarcinoma patients. Patients with dysplasia on histological examination were excluded. In Northern Ireland, cases of Barrett’s oesophagus were initially identified from pathology reports gathered from throughout Northern Ireland. Endoscopy note review was necessary in most patients to confirm the length of the segment of Barrett’s oesophagus, as length was infrequently recorded on the pathology report. In the Republic of Ireland, clinicians in the Dublin and Cork areas sent details of Barrett’s oesophagus patients who met the inclusion criteria to the research personnel.
Eligible control subjects were adults without a history of oesophageal or other gastro-intestinal cancer or a known diagnosis of Barrett’s oesophagus and were frequency matched, by sex and 5-year age band, to the distribution of oesophageal adenocarcinoma patients. Northern Ireland controls were selected at random from the General Practice Master Index (a province-wide database of all persons registered with a general practitioner) and Republic of Ireland controls were selected at random from four General Practices (two urban and two rural) in the Dublin and Cork areas chosen by the researchers to reflect the urban/rural distribution of oesophageal adenocarcinoma patients in the Republic of Ireland.
Participants underwent a structured interview with trained interviewers after giving informed written consent. Information obtained included data on symptoms of gastro-oesophageal reflux (questions based on a translation of those used by Lagergren et al in their Swedish case-control study), weight 5 years before the interview, height and weight at age 21, maximum and minimum weight during adulthood, smoking history, education, occupation and alcohol consumption. Anthropometric measures (height, weight, waist and hip circumference) were taken at the time of interview.
Frequent gastro-oesophageal reflux was defined as symptoms of heartburn and/or acid reflux occurring more than 50 times per year (at least once per week), more than 5 years prior to the interview. Frequent gastro-oesophageal reflux, which prevented subjects from going to sleep or awoke them from sleep, was classified as nocturnal gastro-oesophageal reflux symptoms. The reflux symptom score used by Lagergren et al was applied to the FINBAR dataset but scores 1-4 were combined in the analyses because of the small number of subjects in the first 2 categories.
Current BMI and BMI 5 years before the interview date were calculated by dividing weight in kilograms (current measured and 5-year self-reported, respectively) by current height in metres squared. BMI at age 21 was calculated by dividing self-reported weight in kilograms at age 21 by self-reported height in meters at age 21 squared.
Current smoking status was defined as having smoked at least one cigarette per day for 6 mo or longer, 5 years before the interview date. Previous smokers were those who had quit smoking more than 5 years prior to the interview date. People who had never smoked, and those who had smoked less than 100 cigarettes in their lifetime, or less than one cigarette per day for 6 mo or longer were defined as never smokers. Pack years of smoking were calculated by multiplying the number of cigarettes smoked per day by the number of years of smoking, and dividing by 20. Cigar and pipe smokers were those who had ever smoked at least one cigar or one pipe-full of tobacco per week irrespective of whether they smoked cigarettes.
Fruit, vegetable and energy intake were measured using the European Prospective Investigation of Cancer (EPIC) food frequency questionnaire used in the Norfolk area of England as part of a large European cancer cohort study. This validated questionnaire was modified for the Irish population by including foods commonly eaten in Ireland as identified in the recent North/South Food Consumption Survey. Fruit and vegetable consumption 5 years prior to the interview date were quantified in terms of the sum of the frequencies that each item of fruit/vegetable was eaten per week.
Throughout the article exposures of interest are presented in tertiles. Tertiles of BMI, for example, were calculated from the normal control group with all subjects categorised according to these tertiles. Statistical analyses were performed using STATA 8.0. Chi-square tests were used to examine differences between groups for categorical variables and t-tests were used for continuous variables. Unconditional maximum-likelihood multinomial (polytomous) logistic regression analyses were undertaken to examine the associations between the exposure variables of interest and case/control status adjusting for potential confounders; odds ratios (OR) with 95% confidence intervals (CI) were calculated. Analyses are shown adjusted for potential confounders, including sex, age at interview, job type (manual, non-manual work), education (years full-time) and alcohol consumption (grams per week). Further adjustment was made for gastro-oesophageal reflux symptoms (never, ever), smoking (current, ex-, never), BMI (5 years before diagnosis/interview) and total energy intake (in kilocalories) where appropriate.
Ethical approval for the FINBAR study was obtained from the Research Ethics Committee of the Queen’s University Belfast, the Clinical Research Ethics Committee of the Cork Teaching Hospitals and the Research Ethics Committee Board of St. James’s Hospital, Dublin.
Two hundred and twenty-four Barrett’s oesophagus patients, 227 oesophageal adenocarcinoma patients and 260 controls were recruited. One hundred and thirty-one (57.7%) of the oesophageal adenocarcinoma patients were classified as having oesophageal tumours, ninety-two (40.5%) were classified as junctional tumours and insufficient evidence was available to classify the position of 4 (1.8%) tumours. Characteristics of patients and controls are shown in Table 1.
Table 1 Characteristics of controls, Barrett’s and oesophageal adenocarcinoma patients.
The participation rate of eligible, alive oesophageal adenocarcinoma patients was 74.2% and the overall response rate was 63.9%. The participation rates among Barrett’s oesophagus patients and controls were 82.4% and 41.8%, respectively.
Symptoms of gastro-oesophageal reflux more than 5 years prior to the interview date were strongly associated with Barrett’s oesophagus and to a lesser extent with oesophageal adenocarcinoma (Table 2). In total 72.8% of Barrett’s patients, 48.5% of oesophageal adenocarcinoma patients and 18.9% of controls reported at least weekly symptoms of gastro-oesophageal reflux. Barrett’s oesophagus and oesophageal adenocarcinoma patients were more likely than controls to report nocturnal gastro-oesophageal reflux symptoms, although in the oesophageal adenocarcinoma group the association did not hold for those with junctional tumours (chi-square test, P = 0.001).
Table 2 Comparison of gastro-oesophageal reflux symptoms between controls and Barrett’s oesophagus and oesophageal adenocarcinoma patients and between oesophageal and junctional tumour subgroups.
1Adjusted for sex, age at interview date, body mass index (5 yr prior to the interview date), smoking status (never, ex-, current), alcohol intake (grams), years of full-time education and job type (manual, non-manual).
2Symptoms of heartburn and/or reflux more than 50 times per year.
3Symptoms of GOR that prevented sleep or woke the person from sleep.
4Reflux symptom score. Heartburn or regurgitation only = 1 point, GOR symptoms 2 to 6 times per week = 1 point, heartburn and regurgitation = 1.5 points, nightly symptoms = 2 points, GOR symptoms 7 to 15 times per week = 2 points, symptoms more than 15 times per week = 3 points.
Using the symptom scoring system developed by Lagergren et al Barrett’s patients were 18 times, and oesophageal adenocarcinoma patients more than 3 times, as likely as controls to have a score in the highest gastro-oesophageal reflux category. Patients defined as having oesophageal tumours experienced more severe gastro-oesophageal reflux than patients defined as having junctional tumours. Barrett’s oesophagus and oesophageal adenocarcinoma patients were more likely to have suffered from gastro-oesophageal reflux on a more frequent basis and for a longer duration of time than controls (Table 2).
Body mass index
The associations between BMI (in tertiles) and risk of Barrett’s oesophagus and oesophageal adenocarcinoma at the time of interview are displayed in Table 3. No associations were observed between Barrett’s oesophagus and BMI at any stage (current, at 5 years prior to the interview date or at age 21). Current BMI was significantly lower in oesophageal adenocarcinoma patients than in controls, most likely due to cancer-associated weight loss. However, high BMI 5 years prior to the interview date was associated with a more than 2-fold increased risk of oesophageal adenocarcinoma. The association was similar (highest tertile vs lowest) for tumours classified as oesophageal [OR 2.54 (95% CI 1.44 to 4.48)] or junctional [OR 2.95 (95% CI 1.52 to 5.72]. Oesophageal adenocarcinoma patients were also more likely than controls to be in the highest tertile of BMI at age 21 and to have a higher maximum and minimum weight than controls. Adjusting any of the BMI analyses for a history of gastro-oesophageal reflux symptoms did not significantly alter the observed associations (Table 3).
Table 3 Body mass index and weight comparisons between controls and Barrett’s oesophagus and oesophageal adenocarcinoma patients.
1Adjusted for sex, age at interview date, smoking status (never, ex-, current), alcohol intake (grams), years of full-time education and job type (manual, non-manual).
2Also adjusted for height (centimetres). bP≤ 0.001.
Similar results were observed when BMI was categorised according to the World Health Organisation classification system. Barrett’s oesophagus patients were no more likely than controls to be currently overweight (25-30 kg/m2) [OR 0.86 (95% CI 0.55 to 1.36)] or obese (> 30 kg/m2) [OR 1.06 (95% CI 0.62 to 1.81)] or to have been overweight or obese 5 years before the interview date [OR 0.95 (95% CI 0.62 to 1.45)] and [OR 0.80 (95% CI 0.47 to 1.38) respectively]. Oesophageal adenocarcinoma patients were currently less overweight/obese than controls [OR 0.36 (95% CI 0.23 to 0.57) and OR 0.39 (95% CI 0.22 to 0.69), respectively], but were more likely to have been overweight or obese 5 years before the interview date [OR 1.55 (95% CI 0.96 to 2.50) and OR 2.55 (95% CI 1.47 to 4.41) respectively].
Waist-hip ratio was measured at the time of interview, and no relationship was observed between waist-hip ratio and oesophageal adenocarcinoma [(highest tertile vs lowest) OR 0.80 (95% CI 0.50 to 1.28)] or Barrett’s oesophagus [OR 1.09 (95% CI 0.68 to 1.73)].
Fruit and vegetable intake
Barrett’s oesophagus patients appeared to be less likely than controls to consume fruit and/or vegetables (Table 4). However, following adjustment for gastro-oesophageal reflux symptoms neither fruit nor vegetable intake alone was significantly associated with Barrett’s oesophagus. Compared to controls oesophageal adenocarcinoma patients had a lower intake of fruit, but not vegetables (Table 4). There was no significant difference in the consumption of fruit and vegetables between the oesophageal and junctional subgroups (chi-squared test, P = 0.691).
Table 4 Comparison of fruit and vegetable consumption (5 yr before interview date) between controls and Barrett’s oesophagus and oesophageal adenocarcinoma patients.
1Adjusted for sex, age at interview date, smoking status (never, ex-, current), alcohol intake (grams), energy intake (kilocalories), body mass index (5 yr prior to interview), years of full-time education and job type (manual, non-manual).
Cigarette Smoking was not significantly associated with Barrett's oesophagus; however there was a strong relationship between smoking and oesophageal adenocarcinoma (Table 5). The findings remained significant regardless of the method of smoking categorisation. Adjusting for symptoms of gastro-oesophageal reflux did not significantly alter the observed associations. Ex-smoking and current smoking status 5 years prior to interview were similar in both the oesophageal [OR 1.86 (95% CI 1.05 to 3.30) and OR 4.62 (95% CI 2.40 to 8.91) respectively] and junctional subgroups [OR 1.80 (95% CI 0.95 to 3.42) and OR 4.68 (95% CI 2.40 to 8.91) respectively, chi-square test, P = 0.951]. Neither pipe smoking nor cigar smoking was significantly associated with oesophageal adenocarcinoma or Barrett’s oesophagus (Table 5).
Table 5 Smoking in controls, Barrett’s oesophagus and oesophageal adenocarcinoma patients.
1Adjusted for sex, age at interview date, body mass index 5 yr prior to the interview date, alcohol intake (grams), years of full-time education and job type (manual, non-manual).
2Never smoked, smoked less than 100 cigarettes in lifetime or smoked less than 1 cigarette per day for 6 mo in their lifetime
3Adjusted for use of other tobacco products e.g. cigarettes, pipe or cigar respectively.
This is the first reported population-based case-control study to compare risk factors for both Barrett’s oesophagus and oesophageal adenocarcinoma. The study confirms established risk factors for oesophageal adenocarcinoma and demonstrates important differences between Barrett's oesophagus and oesophageal adenocarcinoma in their association with these factors. Gastro-oesophageal reflux symptoms were strongly associated with Barrett's oesophagus and to a lesser extent with oesophageal adenocarcinoma. A high BMI, 5 years prior to the interview date, and smoking were significantly associated with an increased risk of oesophageal adenocarcinoma but not Barrett’s oesophagus. Barrett’s oesophagus patients appeared to eat less fruit and vegetables than controls. A diet high in fruit but not in vegetables was associated with a reduced risk of oesophageal adenocarcinoma. These data may suggest that gastro-oesophageal reflux symptoms and possibly a diet low in fruit and vegetables are initially responsible for the development of Barrett’s oesophagus, and that obesity and smoking are involved in the progression of Barrett’s oesophagus to oesophageal adenocarcinoma.
The strengths of the FINBAR study are its population-based design, the rapid case ascertainment and stringent inclusion criteria for Barrett’s oesophagus (specialised intestinal metaplasia, length ≥ 3 centimetres) which minimise the inclusion of subjects with a biopsy from an unrecognized hiatus hernia.
In this study, cancers were divided into two subgroups: oesophageal tumours (which could encroach on, but not involve, the oesophagogastric junction) and tumours involving the oesophagus, oesophagogastric junction and gastric cardia (termed junctional tumours). There was a potential weakness for some misclassification of oesophageal adenocarcinoma patients in this study as it was impossible to determine whether junctional tumours are truly gastric or oesophageal in origin.
A potential weakness of the study was the low response rate amongst controls, which may have introduced selection bias. However, controls were similar to the general population with regards to symptoms of gastro-oesophageal reflux and BMI. In a study from Bristol, 15.6% of people aged 20-59 had weekly symptoms of heartburn compared to 18.4% of controls within this age range in the FINBAR study. If gastro-oesophageal reflux symptoms were over-represented in controls then the actual associations between gastro-oesophageal reflux, Barrett’s oesophagus and oesophageal adenocarcinoma may be stronger than observed in this study. The mean weight and the proportion of the obese controls were similar to those seen in the all-Ireland Food Consumption Survey (1997 to 1999). Mean BMI in males aged 51-64 years in the survey was 27.6 kg/m2 (s.d. 3.6 kg/m2) and in FINBAR 28.0 kg/m2 (s.d. 4.5 kg/m2). Similarly, 20% of men were obese (BMI > 30.0 kg/m2) in the Food Consumption Survey compared to 22% of FINBAR male controls. However, in the 2001 Northern Ireland health and social wellbeing survey 23.6% of males at the age of 55 years or over were current smokers, 53.1% ex-smokers and 23.3% non-smokers compared to 18.9%, 48% and 31.1% respectively in FINBAR controls. Non-smokers may be overrepresented among FINBAR controls which could lead to an overestimation of the positive association between oesophageal adenocarcinoma and smoking.
The main predisposing risk factor for Barrett’s oesophagus is gastro-oesophageal reflux. Our finding of a strong association between gastro-oesophageal reflux symptoms and Barrett’s oesophagus is in agreement with a previous case-control study by Conio et al. Since the main presenting symptom for Barrett’s oesophagus is gastro-oesophageal reflux it is possible that diagnosed Barrett’s oesophagus patients are not representative of all Barrett’s patients with regards to gastro-oesophageal reflux symptoms. The association is likely causal in nature; however there may be an overestimation of the true association between gastro-oesophageal reflux and Barrett’s oesophagus. Although the exact mechanisms by which gastro-oesophageal reflux causes Barrett’s oesophagus are still not fully understood, reflux of acid and/or bile into the distal oesophagus is believed to damage the native squamous epithelium and result in re-epithelisation with columnar mucosa. The strength of the relationship between gastro-oesophageal reflux symptoms and oesophageal adenocarcinoma, is in keeping with the findings of several studies on Barrett’s oesophagus[17,23,48] except that of Lagergren et al who reported an OR of 7.7. Our data suggest that although gastro-oesophageal reflux is common in patients with tumours classified as either oesophageal or junctional, those with junctional tumours seem to have less severe symptoms. In particular, nocturnal symptoms of gastro-oesophageal reflux are more strongly associated with oesophageal but not with junctional tumours.
Obesity has been linked with the development of gastro-oesophageal reflux[45,49,50], increased intra-abdominal pressures[54,55] and relaxation of the lower oesophageal sphincter which may worsen gastro-oesophageal reflux symptoms. Obesity has been increasing in incidence[51-53], paralleling the increasing incidence of oesophageal adenocarcinoma[2-6].
Some studies have suggested that a high BMI is associated with an increased risk of Barrett’s oesophagus[22,57,58], although Caygill et al suggested that obesity is only a risk factor for Barrett’s oesophagus in young people. No associations were observed between current BMI, BMI 5 years prior to the interview date, or BMI at age 21, and Barrett’s oesophagus in the FINBAR study. It is possible that the BMI of controls was higher than that of the population which could explain the fact that no association was observed. However, a high BMI 5 years prior to the interview date was associated with a 2.5 fold increased risk of oesophageal adenocarcinoma, which is similar to reports in other case-control studies[24,32-34,59]. If BMI is not associated with Barrett’s oesophagus then one possible mechanism for the association between BMI and oesophageal adenocarcinoma may be through the increased production of free insulin-like growth factor-1 in obese subjects, which stimulates cell proliferation and inhibits apoptosis[60,61]. Sohda et al suggested that increased free insulin-like growth factor-1 may be associated with the development of oesophageal cancer. In Barrett’s patients increased expression of insulin-like growth factor-1 receptor is associated with neoplastic progression.
Fruit, although not vegetable intake was significantly associated with a reduced risk of oesophageal adenocarcinoma in this study. A diet high in fruit and vegetables has been shown to be able to protect against a number of cancers, including cancers of the digestive tract. Several case-control studies have specifically reported positive associations between high fruit and/or vegetable intake and a reduced risk of oesophageal adenocarcinoma[16,24,36-38] and a cohort study recently reported a non-significant inverse association between oesophageal adenocarcinoma and vegetables and citrus fruit. In the FINBAR study vegetable consumption was not associated with a reduced risk of oesophageal adenocarcinoma in fact the OR was raised [OR 1.49 (95% CI 0.89 to 2.48)]. One possible explanation for the apparent protective effect of fruit against oesophageal adenocarcinoma may be that patients with gastro-oesophageal reflux avoid certain fruits which can aggravate their symptoms. However, the protective association between fruit (and overall fruit/vegetable) consumption and oesophageal adenocarcinoma remains after adjustment for gastro-oesophageal reflux symptoms. Fruit and vegetables are high in anti-oxidants, especially in vitamin C, dietary intake of which is reduced in oesophageal adenocarcinoma patients[38,67-70]. Tissue levels of vitamin C are also lower in areas of specialised intestinal metaplasia than in squamous mucosa suggesting that oxidative stress may be implicated in the neoplastic progression of Barrett’s oesophagus. Reflux of gastric contents into the oesophagus can enhance the production of free radicals which may cause damage to lipids, proteins and DNA through oxidative stress and may be implicated in the development of Barrett’s oesophagus and/or oesophageal adenocarcinoma.
Smoking has been associated with an increase in gastro-oesophageal reflux symptoms in some studies[50,72,73], but not in others[20,58,74,75]. Unlike Smith et al we observed no significant association between smoking and Barrett’s oesophagus in the FINBAR study. There was a strong relationship between smoking and oesophageal adenocarcinoma with a slightly higher OR than observed in previous studies[13,15,16,18,19,35,76]. The under-representation of current smokers among FINBAR controls may tend to overestimate the association between smoking and oesophageal adenocarcinoma/Barrett’s oesophagus but should not affect the difference in ORs seen between the two conditions. Our data suggest that smoking may influence the progression of Barrett’s oesophagus to oesophageal adenocarcinoma and not the initiation of Barrett’s oesophagus. One possible explanation may be that the higher rate of cell division and proliferation of columnar epithelial cells and the malignant potential that such cells possess, may be promoted by carcinogenic (or DNA damaging) compounds from cigarette smoke. Olliver et al showed that Barrett’s mucosa has higher levels of DNA damage than squamous epithelium and smoking is associated with increased DNA damage in Barrett’s mucosa.
In conclusion, our data indicate that gastro-oesophageal reflux is a risk factor for oesophageal adenocarcinoma and demonstrate the high proportion of diagnosed Barrett's patients with gastro-oesophageal reflux symptoms. In the FINBAR study oesophageal adenocarcinoma differs from Barrett’s oesophagus by being associated with high BMI and smoking. These factors could be implicated in the development of oesophageal adenocarcinoma from Barrett’s oesophagus although further observational and interventional studies are required to confirm or refute our findings. It is hoped that these findings will help direct future research into the mechanisms underlying oesophageal adenocarcinoma and the development of prevention strategies.
We appreciate the contributions made by the study participants and their families. We would like to thank the clinicians who were contacted throughout the study period and their secretaries for administrative support. Thanks also to the research team including Siobhan Reynolds, Majella Gallagher, Carol Anderson and Martin McAnaespie and to Dr Damian McManus who helped in classifying the tumour sites. Thanks to the Northern Ireland Cancer Registry and National Cancer Registry Cork for their support and involvement in the research.
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Ruol A, Parenti A, Zaninotto G, Merigliano S, Costantini M, Cagol M, Alfieri R, Bonavina L, Peracchia A, Ancona E. Intestinal metaplasia is the probable common precursor of adenocarcinoma in barrett esophagus and adenocarcinoma of the gastric cardia.Cancer. 2000;88:2520-2528.
Hansson LE, Sparén P, Nyrén O. Increasing incidence of both major histological types of esophageal carcinomas among men in Sweden.Int J Cancer. 1993;54:402-407.
Botterweck AA, Schouten LJ, Volovics A, Dorant E, van Den Brandt PA. Trends in incidence of adenocarcinoma of the oesophagus and gastric cardia in ten European countries.Int J Epidemiol. 2000;29:645-654.
Powell J, McConkey CC. The rising trend in oesophageal adenocarcinoma and gastric cardia.Eur J Cancer Prev. 1992;1:265-269.
Møller H. Incidence of cancer of oesophagus, cardia and stomach in Denmark.Eur J Cancer Prev. 1992;1:159-164.
Blot WJ, McLaughlin JK. The changing epidemiology of esophageal cancer.Semin Oncol. 1999;26:2-8.
Theisen J, Stein HJ, Dittler HJ, Feith M, Moebius C, Kauer WK, Werner M, Siewert JR. Preoperative chemotherapy unmasks underlying Barrett's mucosa in patients with adenocarcinoma of the distal esophagus.Surg Endosc. 2002;16:671-673.
Murray L, Watson P, Johnston B, Sloan J, Mainie IM, Gavin A. Risk of adenocarcinoma in Barrett's oesophagus: population based study.BMJ. 2003;327:534-535.
Drewitz DJ, Sampliner RE, Garewal HS. The incidence of adenocarcinoma in Barrett's esophagus: a prospective study of 170 patients followed 4.8 years.Am J Gastroenterol. 1997;92:212-215.
Rana PS, Johnston DA. Incidence of adenocarcinoma and mortality in patients with Barrett's oesophagus diagnosed between 1976 and 1986: implications for endoscopic surveillance.Dis Esophagus. 2000;13:28-31.
O'Connor JB, Falk GW, Richter JE. The incidence of adenocarcinoma and dysplasia in Barrett's esophagus: report on the Cleveland Clinic Barrett's Esophagus Registry.Am J Gastroenterol. 1999;94:2037-2042.
Katz D, Rothstein R, Schned A, Dunn J, Seaver K, Antonioli D. The development of dysplasia and adenocarcinoma during endoscopic surveillance of Barrett's esophagus.Am J Gastroenterol. 1998;93:536-541.
Gammon MD, Schoenberg JB, Ahsan H, Risch HA, Vaughan TL, Chow WH, Rotterdam H, West AB, Dubrow R, Stanford JL. Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia.J Natl Cancer Inst. 1997;89:1277-1284.
Lagergren J, Bergström R, Lindgren A, Nyrén O. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma.N Engl J Med. 1999;340:825-831.
Wu AH, Wan P, Bernstein L. A multiethnic population-based study of smoking, alcohol and body size and risk of adenocarcinomas of the stomach and esophagus (United States).Cancer Causes Control. 2001;12:721-732.
Cheng KK, Sharp L, McKinney PA, Logan RF, Chilvers CE, Cook-Mozaffari P, Ahmed A, Day NE. A case-control study of oesophageal adenocarcinoma in women: a preventable disease.Br J Cancer. 2000;83:127-132.
Chow WH, Finkle WD, McLaughlin JK, Frankl H, Ziel HK, Fraumeni JF. The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia.JAMA. 1995;274:474-477.
Brown LM, Silverman DT, Pottern LM, Schoenberg JB, Greenberg RS, Swanson GM, Liff JM, Schwartz AG, Hayes RB, Blot WJ. Adenocarcinoma of the esophagus and esophagogastric junction in white men in the United States: alcohol, tobacco, and socioeconomic factors.Cancer Causes Control. 1994;5:333-340.
Kabat GC, Ng SK, Wynder EL. Tobacco, alcohol intake, and diet in relation to adenocarcinoma of the esophagus and gastric cardia.Cancer Causes Control. 1993;4:123-132.
Conio M, Filiberti R, Blanchi S, Ferraris R, Marchi S, Ravelli P, Lapertosa G, Iaquinto G, Sablich R, Gusmaroli R. Risk factors for Barrett's esophagus: a case-control study.Int J Cancer. 2002;97:225-229.
Ritenbaugh C, Sampliner R, Aickin M, Garewal H, Meyskens F. Risk factors for Barrett's oesophagus: a life history approach to behavioural assessment in the distant past.Eur J Cancer Prev. 1995;4:459-468.
El-Serag HB, Kvapil P, Hacken-Bitar J, Kramer JR. Abdominal obesity and the risk of Barrett's esophagus.Am J Gastroenterol. 2005;100:2151-2156.
Farrow DC, Vaughan TL, Sweeney C, Gammon MD, Chow WH, Risch HA, Stanford JL, Hansten PD, Mayne ST, Schoenberg JB. Gastroesophageal reflux disease, use of H2 receptor antagonists, and risk of esophageal and gastric cancer.Cancer Causes Control. 2000;11:231-238.
Brown LM, Swanson CA, Gridley G, Swanson GM, Schoenberg JB, Greenberg RS, Silverman DT, Pottern LM, Hayes RB, Schwartz AG. Adenocarcinoma of the esophagus: role of obesity and diet.J Natl Cancer Inst. 1995;87:104-109.
Pera M. Trends in incidence and prevalence of specialized intestinal metaplasia, barrett's esophagus, and adenocarcinoma of the gastroesophageal junction.World J Surg. 2003;27:999-1008; discussion 1006-1008.
Lieberman DA, Oehlke M, Helfand M. Risk factors for Barrett's esophagus in community-based practice. GORGE consortium. Gastroenterology Outcomes Research Group in Endoscopy.Am J Gastroenterol. 1997;92:1293-1297.
Mann NS, Tsai MF, Nair PK. Barrett's esophagus in patients with symptomatic reflux esophagitis.Am J Gastroenterol. 1989;84:1494-1496.
Cameron AJ, Zinsmeister AR, Ballard DJ, Carney JA. Prevalence of columnar-lined (Barrett's) esophagus. Comparison of population-based clinical and autopsy findings.Gastroenterology. 1990;99:918-922.
Bytzer P, Christensen PB, Damkier P, Vinding K, Seersholm N. Adenocarcinoma of the esophagus and Barrett's esophagus: a population-based study.Am J Gastroenterol. 1999;94:86-91.
Cameron AJ, Ott BJ, Payne WS. The incidence of adenocarcinoma in columnar-lined (Barrett's) esophagus.N Engl J Med. 1985;313:857-859.
Dulai GS, Guha S, Kahn KL, Gornbein J, Weinstein WM. Preoperative prevalence of Barrett's esophagus in esophageal adenocarcinoma: a systematic review.Gastroenterology. 2002;122:26-33.
Lagergren J, Bergström R, Nyrén O. Association between body mass and adenocarcinoma of the esophagus and gastric cardia.Ann Intern Med. 1999;130:883-890.
Chow WH, Blot WJ, Vaughan TL, Risch HA, Gammon MD, Stanford JL, Dubrow R, Schoenberg JB, Mayne ST, Farrow DC. Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia.J Natl Cancer Inst. 1998;90:150-155.
Vaughan TL, Davis S, Kristal A, Thomas DB. Obesity, alcohol, and tobacco as risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma versus squamous cell carcinoma.Cancer Epidemiol Biomarkers Prev. 1995;4:85-92.
Lagergren J, Bergström R, Lindgren A, Nyrén O. The role of tobacco, snuff and alcohol use in the aetiology of cancer of the oesophagus and gastric cardia.Int J Cancer. 2000;85:340-346.
Terry P, Lagergren J, Hansen H, Wolk A, Nyrén O. Fruit and vegetable consumption in the prevention of oesophageal and cardia cancers.Eur J Cancer Prev. 2001;10:365-369.
Chen H, Ward MH, Graubard BI, Heineman EF, Markin RM, Potischman NA, Russell RM, Weisenburger DD, Tucker KL. Dietary patterns and adenocarcinoma of the esophagus and distal stomach.Am J Clin Nutr. 2002;75:137-144.
Tzonou A, Lipworth L, Garidou A, Signorello LB, Lagiou P, Hsieh C, Trichopoulos D. Diet and risk of esophageal cancer by histologic type in a low-risk population.Int J Cancer. 1996;68:300-304.
Engel LS, Chow WH, Vaughan TL, Gammon MD, Risch HA, Stanford JL, Schoenberg JB, Mayne ST, Dubrow R, Rotterdam H. Population attributable risks of esophageal and gastric cancers.J Natl Cancer Inst. 2003;95:1404-1413.
Anderson LA, Johnston BT, Watson RG, Murphy SJ, Ferguson HR, Comber H, McGuigan J, Reynolds JV, Murray LJ. Nonsteroidal anti-inflammatory drugs and the esophageal inflammation-metaplasia-adenocarcinoma sequence.Cancer Res. 2006;66:4975-4982.
Day N, Oakes S, Luben R, Khaw KT, Bingham S, Welch A, Wareham N. EPIC-Norfolk: study design and characteristics of the cohort. European Prospective Investigation of Cancer.Br J Cancer. 1999;80 Suppl 1:95-103.
Harrington KE, Robson PJ, Kiely M, Livingstone MB, Lambe J, Gibney MJ. The North/South Ireland Food Consumption Survey: survey design and methodology.Public Health Nutr. 2001;4:1037-1042.
StataCorp . Stata Statistical Software: Release 8.0. College Station. TX: Stata Corporation; .
Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee.World Health Organ Tech Rep Ser. 1995;854:1-452.
Murray L, Johnston B, Lane A, Harvey I, Donovan J, Nair P, Harvey R. Relationship between body mass and gastro-oesophageal reflux symptoms: The Bristol Helicobacter Project.Int J Epidemiol. 2003;32:645-650.
McCarthy SN, Harrington KE, Kiely M, Flynn A, Robson PJ, Livingstone MB, Gibney MJ. Analyses of the anthropometric data from the North/South Ireland Food Consumption Survey.Public Health Nutr. 2001;4:1099-1106.
Northern Ireland Statistics and Research Agency. Northern Ireland Health and Social Well-being Survey, 2001.
Available from: http: //www.nisra.gov.uk.
Wu AH, Tseng CC, Bernstein L. Hiatal hernia, reflux symptoms, body size, and risk of esophageal and gastric adenocarcinoma.Cancer. 2003;98:940-948.
Nilsson M, Johnsen R, Ye W, Hveem K, Lagergren J. Obesity and estrogen as risk factors for gastroesophageal reflux symptoms.JAMA. 2003;290:66-72.
Mokdad AH, Serdula MK, Dietz WH, Bowman BA, Marks JS, Koplan JP. The spread of the obesity epidemic in the United States, 1991-1998.JAMA. 1999;282:1519-1522.
Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000.JAMA. 2002;288:1723-1727.
McCarthy SN, Gibney MJ, Flynn A. Overweight, obesity and physical activity levels in Irish adults: evidence from the North/South Ireland food consumption survey.Proc Nutr Soc. 2002;61:3-7.
Barak N, Ehrenpreis ED, Harrison JR, Sitrin MD. Gastro-oesophageal reflux disease in obesity: pathophysiological and therapeutic considerations.Obes Rev. 2002;3:9-15.
Sugerman HJ, DeMaria EJ, Felton WL, Nakatsuka M, Sismanis A. Increased intra-abdominal pressure and cardiac filling pressures in obesity-associated pseudotumor cerebri.Neurology. 1997;49:507-511.
Kouklakis G, Moschos J, Kountouras J, Mpoumponaris A, Molyvas E, Minopoulos G. Relationship between obesity and gastroesophageal reflux disease as recorded by 3-hour esophageal pH monitoring.Rom J Gastroenterol. 2005;14:117-121.
Smith KJ, O'Brien SM, Smithers BM, Gotley DC, Webb PM, Green AC, Whiteman DC. Interactions among smoking, obesity, and symptoms of acid reflux in Barrett's esophagus.Cancer Epidemiol Biomarkers Prev. 2005;14:2481-2486.
Caygill CP, Johnston DA, Lopez M, Johnston BJ, Watson A, Reed PI, Hill MJ. Lifestyle factors and Barrett's esophagus.Am J Gastroenterol. 2002;97:1328-1331.
Mayne ST, Navarro SA. Diet, obesity and reflux in the etiology of adenocarcinomas of the esophagus and gastric cardia in humans.J Nutr. 2002;132:3467S-3470S.
Calle EE, Thun MJ. Obesity and cancer.Oncogene. 2004;23:6365-6378.
Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms.Nat Rev Cancer. 2004;4:579-591.
Sohda M, Kato H, Miyazaki T, Nakajima M, Fukuchi M, Manda R, Fukai Y, Masuda N, Kuwano H. The role of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 in human esophageal cancer.Anticancer Res. 2004;24:3029-3034.
Iravani S, Zhang HQ, Yuan ZQ, Cheng JQ, Karl RC, Jove R, Coppola D. Modification of insulin-like growth factor 1 receptor, c-Src, and Bcl-XL protein expression during the progression of Barrett's neoplasia.Hum Pathol. 2003;34:975-982.
Riboli E, Norat T. Epidemiologic evidence of the protective effect of fruit and vegetables on cancer risk.Am J Clin Nutr. 2003;78:559S-569S.
Norat T, Riboli E. Fruit and vegetable consumption and risk of cancer of the digestive tract: meta-analysis of published case-control and cohort studies.IARC Sci Publ. 2002;156:123-125.
González CA, Pera G, Agudo A, Bueno-de-Mesquita HB, Ceroti M, Boeing H, Schulz M, Del Giudice G, Plebani M, Carneiro F. Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST).Int J Cancer. 2006;118:2559-2566.
Chen H, Tucker KL, Graubard BI, Heineman EF, Markin RS, Potischman NA, Russell RM, Weisenburger DD, Ward MH. Nutrient intakes and adenocarcinoma of the esophagus and distal stomach.Nutr Cancer. 2002;42:33-40.
Mayne ST, Risch HA, Dubrow R, Chow WH, Gammon MD, Vaughan TL, Farrow DC, Schoenberg JB, Stanford JL, Ahsan H. Nutrient intake and risk of subtypes of esophageal and gastric cancer.Cancer Epidemiol Biomarkers Prev. 2001;10:1055-1062.
Bollschweiler E, Wolfgarten E, Nowroth T, Rosendahl U, Mönig SP, Hölscher AH. Vitamin intake and risk of subtypes of esophageal cancer in Germany.J Cancer Res Clin Oncol. 2002;128:575-580.
Terry P, Lagergren J, Ye W, Nyrén O, Wolk A. Antioxidants and cancers of the esophagus and gastric cardia.Int J Cancer. 2000;87:750-754.
Fountoulakis A, Martin IG, White KL, Dixon MF, Cade JE, Sue-Ling HM, Wild CP. Plasma and esophageal mucosal levels of vitamin C: role in the pathogenesis and neoplastic progression of Barrett's esophagus.Dig Dis Sci. 2004;49:914-919.
Stanciu C, Bennett JR. Smoking and gastro-oesophageal reflux.Br Med J. 1972;3:793-795.
Kahrilas PJ, Gupta RR. Mechanisms of acid reflux associated with cigarette smoking.Gut. 1990;31:4-10.
Gerson LB, Shetler K, Triadafilopoulos G. Prevalence of Barrett's esophagus in asymptomatic individuals.Gastroenterology. 2002;123:461-467.
Reavis KM, Morris CD, Gopal DV, Hunter JG, Jobe BA. Laryngopharyngeal reflux symptoms better predict the presence of esophageal adenocarcinoma than typical gastroesophageal reflux symptoms.Ann Surg. 2004;239:849-56; discussion 856- 858.
Garidou A, Tzonou A, Lipworth L, Signorello LB, Kalapothaki V, Trichopoulos D. Life-style factors and medical conditions in relation to esophageal cancer by histologic type in a low-risk population.Int J Cancer. 1996;68:295-299.
Halm U, Tannapfel A, Breitung B, Breidert M, Wittekind CW, Mössner J. Apoptosis and cell proliferation in the metaplasia-dysplasia-carcinoma-sequence of Barrett's esophagus.Hepatogastroenterology. 2000;47:962-966.
Preston-Martin S, Pike MC, Ross RK, Jones PA, Henderson BE. Increased cell division as a cause of human cancer.Cancer Res. 1990;50:7415-7421.
Olliver JR, Hardie LJ, Gong Y, Dexter S, Chalmers D, Harris KM, Wild CP. Risk factors, DNA damage, and disease progression in Barrett's esophagus.Cancer Epidemiol Biomarkers Prev. 2005;14:620-625.
Olliver JR, Hardie LJ, Dexter S, Chalmers D, Wild CP. DNA damage levels are raised in Barrett's oesophageal mucosa relative to the squamous epithelium of the oesophagus.Biomarkers. 2003;8:509-521.