The role of folate in the aetiology of oesophageal lesions

1. The role of folate in the aetiology of oesophageal lesions L Sharp,1 A-E Carsin,1 L Anderson,2 H Ferguson,2 SJ Murphy,2 A McElholm,2 BT Johnston,3 RGP Watson,3 H Comber,1 J McGuigan,3 JV Reynolds,4 LJ Murray2 1 National Cancer Registry Ireland, Cork; 2 Centre for Clinical and Population Sciences, Queen’s University, Belfast; 3 Royal Group of Hospitals, Belfast; 4 St James’ Hospital, Dublin

2. Folate • B vitamin • Natural sources • green vegetables • oranges • yeast • cereals and grains • Synthetic form = folic acid

3. Key metabolic roles of folate FOLATE deoxyuridine dihydrofolate monophosphate (dUMP) methionine tetrahydrofolateS-adenosyl-homocysteinemethionine (SAM) 5,10-methylene5-methyls-adenosyl tetrahydrofolate tetrahydrofolatehomocysteine (SAH) deoxythymidine monophosphate (dTMP) DNA REPAIR DNA DNA SYNTHESIS METHYLATION

4. Other factors influencing folate metabolism Efficient folate metabolism requires other B vitamins • vitamin B12 • vitamin B6 • riboflavin Folate metabolism is affected by • alcohol – inhibits folate absorption • smoking – may impair folate utilisation

5. Oesophageal adenocarcinoma carcinogenesis ? normal inflammation specialized dysplasia malignancy squamous columnar mucosa epithelium reflux Barrett’s adenocarcinoma oesophagitis oesophagus

6. FINBAR (Factors INfluencing the Barrett’s Adenocarcinoma Relationship) case-control study Aim • To investigate risk factors for adenocarcinoma of the oesophagus (OAC), Barrett’s oesophagus (BO) and reflux oesophagitis (RO) Research Questions • Is dietary intake of folate associated with risks of developing OAC, BO or RO? • Are intakes of vitamin B12, vitamin B6 and riboflavin associated with risk? • Are these relationship modified by alcohol intake and/or cigarette smoking? • Are plasma folate, vitamin B12 and homocysteine associated with risk?

7. FINBAR Methods 1 OAC Cases • histologically confirmed disease, diagnosed May 2002-Dec 2004, < 85 years BO Cases • long segment BO (≥3cm), specialised intestinal metaplasia on histology, diagnosed May 2002-Dec 2004, < 85 years RO Cases • Macroscopically visible erosive oesophagitis at endoscopy, aged < 85 years Controls • aged 35-84 years, no history of BO or oesophageal or other GI cancer • selected from Northern Ireland GP Master Index and from GP lists in Dublin and Cork

8. FINBAR Methods 2 Assessment of dietary exposures • structured interview and food frequency questionnaire (EPIC modified for dietary variations in Ireland) • reference period: 5-years prior to interview Assessment of blood exposures • blood sample obtained at interview • plasma folate and vitamin B12 measured by SimulTRAC-SNB radioassay • total homocysteine measured by HPLC Statistical analysis • estimated daily intakes of micronutrients; adjusted for total energy intake • logistic regression to compute multivariate odds ratios (OR) with 95% CIs • separate analyses for OAC, BO and RO

9. Characteristics of participants

10. Folate intake and disease risk 1 cut-points for energy-adjusted residuals: Q1: ≤318.3g/day; Q2: 318.3-370.89 g/day; Q3: 370.90-420.00 g/day; Q4: ≥420.01 g/day 2 multivariate risk estimates

11. Plasma folate and disease risk • Similar associations to those with dietary folate intake ORs adjusted for age, sex, BMI and, for BO and RO, waist-hip ratio

12. Plasma homocysteine and disease risk ORs adjusted for age, sex, BMI and, for BO and RO, waist-hip ratio

13. Other B vitamins Dietary vitamin B6 • Strong inverse associations with OAC, BO and RO Dietary riboflavin • Inversely related to RO; not associated with OAC or BO Vitamin B12 • Dietary intake – strong positive association with OAC (OR Q4 vs Q1=3.9) and BO (OR Q4 vs Q1=2.1), but not RO • Plasma levels – no associations with OAC, BO or RO

14. Folate, smoking and OAC 1 “low” < median (Q1+Q2); “high” ≥ median (Q3+Q4) 2 multivariate ORs

15. Folate, smoking and BO 1 “low” < median (Q1+Q2); “high” ≥ median (Q3+Q4) 2 multivariate ORs

16. Folate, alcohol and oesophageal lesions Alcohol intake (5-years before interview and at age 21) did not significantly modify associations between folate intake and OAC, BO or RO However - risk of disease was highest in those who drank alcohol at age 21 and had low folate intake (i.e. the group expected to have lowest folate status)

17. Conclusions • These results suggest that folate metabolism may have a role in the aetiology of oesophageal lesions • Folate may be important early in the disease process • Confirmation needed of finding that low folate intake may exacerbate effects of smoking on risk • Folate levels in population are potentially amenable to change (dietary change, supplement use, food fortification) • Could folate have a role in prevention of OAC or management/surveillance of individuals with BO or RO?

18. Acknowledgements Northern Ireland: Liam Murray (PI); Carol Anderson; Lesley Anderson;; Geraldine Cuskelly; Anna Gavin; Heather Ferguson; Anne Hughes; Brian Johnston; Martin McAnaespie; Adrian McElholm Ann McGinty; Jim McGuigan; Damian McManus; Seamus Murphy; Peter Watson Republic of Ireland: Harry Comber; Anne-Elie Carsin; Majella Gallagher; Lisa Higgins; Dermot Kelleher; Ross McManus; Gerry O’Sullivan; John Reynolds; Siobhan Reynolds Leeds: Chris Wild; Laura Hardie Leicester:Janusz Jankowski FINBAR was funded by the Northern Ireland Research & Development Office; Health Research Board, Dublin; Ulster Cancer Foundation