1. A. Pourshams M.D Gastroenterologist Tehran University, Tehran, Iran pourshams@ams.ac.ir Gastrointestinal Cancer Epidemiology and Risk Factors Epidemiology and risk factors for Oesophageal Cancer 4. Apr. 2010 Istanbul, Turkey

2. ESCC epidemiology EC Among 10 most ca Almost fatal 2 histological types World : ESCC> EADC ESCC in: Asian EC belt, S. Africa, S. America (France $ UK)* EADC: Western count, Rapidly ↑ in world

3. EADC Barrett GERD SECC Socioeconomic Dietary habits Alcohol Tobacco,Opium Infections Oral hygiene Toxic agents Genetic Risk factors

4. ESCC Protective factors : Formal education water piped into the home Socio-economic status and oesophageal cancer: results from a population-basedcase-control study in a high- risk area[ Iran]. Int J Epidemiol 2009. Prospective Study of Risk Factors for Esophageal and Gastric Cancers in the Linxian General Population Trial Cohort in China. Int. J. Cancer 2005. Socioeconomic

5. ↑ EADC : ever employed in administrative support ; financial, insurance, real estate ; and health services (OR = 2.2) ↑ ESCC : among occupations potentially associated with exposure to silica dust and chemical solvents or detergents No association with farming & pesticide exposure Job strain?? Engel et al. Occupation and risk of esophageal and gastric cardia adenocarcinoma. Am J Ind Med 2002 ;42:11-22. Cucino et al.Occupational mortality from squamous cell carcinoma of the esophagus in the United States during 1991-1996. Dig Dis Sci. 2002 ;47:568-72 Occupation

6. EC Dietary habit ↑ levels of N- nitroso fried foods preserved processed hot or boiled rapidly eating salted food pickle butter Saturated fats animal fats fish juice CANCER Pipe water Meat, poultry Egg Fresh Fruits Raw vegetable green tea ? pasta and rice vitamin supplement s ? olive oil dietary fiber? fish Risk factors Protective

7. EC Dietary habit I. a diet deficient in fruits and vegetables (Cook-Mozaffari et al, 1979 & again DDRC group in 2009) II. a thermal injury from consumption of very hot beverages (Cook-Mozaffari et al, 1979; Ghadirian,1987) Tea drinking habits and oesophageal cancer in high risk area in northern Iran: population based case-control study. Islami F, Pourshams A, et al. BMJ 2009.

8. Alcohol,Tobacco: ? Opium consumption : (Joint Iran-IARC Study Group, 1977; Dowlatshahi and Miller, 1985; Ghadirian et al, 1985,Tehran DDRC group 2009) Alcohol, Tobacco & Opium EC

9. –Absence of H. pylori ? ~↑EADC Helicobacter pylori and esophageal cancer risk: a meta-analysis. Islami F, et al. Cancer Prev Res 2008: inverse association between Cag A- positive H. pylori colonization and risk of EADC. –HPV ? –Fumonisins ? Infections Iran & China studies

10. ESCC Tooth loss & lack of regular oral hygiene are associated with higher risk of ESCC. Iran & China studies Oral hygiene

11. Polycyclic Aromatic Hydrocarbons (PAHs) Present in tobacco smoke, cooked food, automobile exhaust etc. Act as cancer initiators and promoters Metabolism may activate or detoxify PAHs There are suggestions of high exposure in high risk populations Benzo (a) pyrene Toxic agents

12. High exposure to polycyclic aromatic hydrocarbons may contribute to high risk of esophageal cancer in northeastern Iran. Anticancer Res 2005. Dietary intake of benzo(a)pyrene and risk of esophageal cancer in north of Iran. Nutr Cancer 2008. High levels of carcinogenic polycyclic aromatic hydrocarbons in mate drinks. Cancer Epidemiol Biomarkers Prev 2008.

13. Genetic & Molecular Enzymes produce by these genes : 1.Cytochromes P450 :bioactivation 2. Glutathione S-transferases : detoxifying 3. Alcohol dehydrogenases & Aldehyde dehydrogenases : alcohol-metabolizing Current data on genetic polymorphisms of these gene & their role for EC developing is still insufficient ! Susceptible genes to chemicals

14. Tumor suppressor genes important role in switch ► from G1 to S by CDKs (cyclin D1 is the key). 1. p 53 ( most common genetic alteration in human cancers & most frequently studied genetic alteration in ESCC) * 10–85% mutation in ESCC * ethnical variation in incidence & patterns 2. p 21: have a role 3. p 16 & p 15: - p16 have a prognostic role - p15 :to be clarified 4. p 27 ~aggressive behavior.

15. Genetic & Molecular I - GF : EGF,TGF a, c-sis Cause cells in G 0 to enter & proceed through cell cycle There is no evidence that growth factors play an important role in EC ! II - GF receptors: erbB- 1, erbB- 2, erbB- 3,erbB- 4 GFR genes translates proteins on cell membrane that act as receptors ►DNA amplification or over-production of mRNA Evidences : erb-B-1 expression is a useful maker for poor prognosis in ESCC Over-production of erb B2 is usually noted in EADC Oncogenes

16. Metastasis related factors 1. Cell adhesion molecules integrin receptors,cadherins,immunoglobulin lectin-like cell,lamin-binding protein,CD44 receptor 2. Enzymes in degradation of extra-cellular matrix matrix metalloproteinase,, plasminogen activator & cathespins More data should be obtained !

17. Apoptosis genes * The most important regulators of apoptosis are the proteins of the bcl- 2 family no important role !

18. Familial risks of esophageal cancer among the Turkmen population of the Caspian littoral of Iran. Int J Cancer 2006.

19. in the Van region of Eastern Turkey probable culprit factors for EC were: Low educational & socioeconomic status smoked, salted, hot, fatty food over drinking hot tea & well water cigarette smoking poor intake of fresh fruits & vegetables poor hygienic conditions Turkdogan et al.Epidemiological aspects of endemic upper gastrointestinal cancers in eastern Turkey. Hepatogastroenterology 2005 ;52:496-500.

20. Our recent studies shows in high risk area of Iran : Socioeconomic level has gone up ESCC is coming down but still is high E AC is increasing Obesity, metabolic syndrome, GERD are very common, is comparable to the western countries not the Asian countries. PAH & oral hygiene should be emphasis

21. Remarks ● There are regional differences in the study populations as a result of exposures to different local environmental risk factors & genetic differences ● Socioeconomic & life style are most important factors