Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

1. Introduction to Medicine 2006/2007 Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review http://www.nlm.nih.gov/ Authors:Catarino, Rosa; Costa, Flávio; Félix, Joana; Leal, Nuno; Mendes, Leonor; Moreira, Helena; Peixoto, Carla; Sampaio, Maria; Santos, Joana; Sequeira, Ana; Sousa, Joel; Tavares, Maria. Supervisors: Mário Dinis-Ribeiro, Altamiro da Costa-Pereira

2. Stomach cancer incidence rates - By sex (Europe) http://health.gov.mt/ministry/dhi/publications/mncr/stomach.htm Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

3. Stomach cancer Survival rates Stomach cancer - five year survival *standardised relative survival for stomach cancer by sex for patients diagnosed in England and Wales during 1971-1999 http://info.cancerresearchuk.org Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

4. Cancer Stomach Cancer Disease in which the body's cells become abnormal and divide without control. Cancer cells may invade nearby tissues and they may spread through the bloodstream and lymphatic system to other parts of the body. Stomach cancer is the growth of cancer cells in the lining and wall of the stomach. Stomach cancers are believed to develop slowly over many years. MEN / WOMEN ENVIRONMENT Risk factor? Polymorphisms of Inflammatory Genes Gastric Cancer Protective factor? http://www.cancer.gov/cancerinfo/wyntk/stomach http://www.nlm.nih.gov/medlineplus/stomachcancer.html Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

5. Polymorphisms of Inflammatory Genes as a gastric cancer’s cause Epidemiological studies show a clear association between chronic inflammatory conditions and subsequent malignant transformation in the inflamed tissue. Chronic inflammation is characterized by infiltration of damaged tissue by mononuclear cells together with tissue destruction and attempts at repair. A cardinal feature of inflamed tissues is the generation of NO and the presence of an inducible enzyme with carcinogenic properties – Cyclooxygenase-2 (COX-2) Among the most potent inducers of COX-2 are the key proinflammatory cytokines IL-1 and TNF. NO, its products, and COX-2 may exert oncogenic effects via several mechanisms http://www.nlm.nih.gov/ Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

6. Polymorphisms of Inflammatory Genes as a gastric cancer’s cause Proinflammatory cytokine gene polymorphisms may increase or reduce the risk of cancer and its precursors. IL-1β, IL-6, TNF-α, CXCL, CCR,COX-2 Genetic polymorphisms directly influence interindividual variation in the magnitude of cytokine response, and this clearly contributes to an individual’s ultimate clinical outcome. Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review Burmester, G. K.; Pezzutto,Color Atlas of Immunology,2003

7. Aim: • To perform a systematic review of studies on risk of gastric cancer associated with genetic polymorphisms related with Cox, TNF and IL-1. Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

8. Methods Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

9. Studydesign • We conducted an exhaustive search for primary studies in a general database – Medline, using the following query: ((risk*[Title/Abstract] OR risk*[MeSH:noexp] OR risk *[MeSH:noexp] OR cohort studies[MeSH Terms] OR group*[Text Word]) OR (incidence[MeSH:noexp] OR mortality[MeSH Terms] OR follow up studies[MeSH:noexp] OR prognos*[Text Word] OR predict*[Text Word] OR course*[Text Word])) AND ((("Polymorphism, Single Nucleotide"[MeSH] OR "Polymorphism, Genetic"[MeSH]) OR polymorphism) AND (("Cyclooxygenase 2"[MeSH] OR "Cyclooxygenase 1"[MeSH]) OR ("Interleukin-1"[MeSH] OR "Receptors, Interleukin-1"[MeSH]) OR "Tumor Necrosis Factor-alpha"[MeSH] OR Cox OR IL-1 OR TNF) AND ("Stomach"[MeSH] OR "Stomach Neoplasms"[MeSH] OR gastric) AND (cancer OR adenocarcinoma)) We have found 86 potential studies. Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

10. Study design • Inclusion Criteria: • Original articles, observational studies, that evaluated the risk of gastric cancer according to Polymorphisms of Inflammatory Genes • Exclusion Criteria: • Case Reports • Case series • Reviews • Language (we only accept articles written in English or French) Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

11. Flow Chart – First Stage Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

12. Flow Chart – Second Stage Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

13. Results Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

14. Quality criteria SELECTION BIAS 1. Did the investigators do any type of blinding? 2.Did the investigators demonstrate similarity in all known determinants of outcome? 3. Did they adjust for differences in the analysis? PERFORMANCE BIAS 4. Were persons responsible for assessing outcome unware of the assigned intervention? 5. Were exposed patients equally likely to be identified in the two groups? ATTRITION BIAS 6. Was follow up sufficiently complete (at least 80%)? DETECTION BIAS 7. Were the outcomes measured in the same way in the groups being compared? Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

15. Quality analysis Y - Yes N - No U - Unknown CC- Case-control C - Cohort Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

16. Quality analysis Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

17. Studies characteristics Polymorphism COX-2 IL-1B-31,-511 IL-1B-511 TNF-alfa-238, 308, 857, 1031 IL-1B-31, +3954, -511 TNF-alfa-308 IL-1B-31, -511, +3954 IL-1B-31, 511 TNF-alfa-308 Local of Study Portugal Japan Poland Germany Italy Italy China China % male gender (cases) 49 73 61 54 58 60 84 73 % male gender (controls) 64 73 48 48 49 53 84 72 Case-controls Pereira C., 2006 Ikehara SK., 2006 Starzynska T., 2006 Hellmig S., 2005 Palli D., 2005 Perri F., 2005 Zhang WH., 2005 Lu W., 2005 Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

18. Studies characteristics % male gender (cases)- 32 85 - - - 37 % male gender (controls) - 68 78 - - - 58 Local of study S Korea UK U.S.A. Portugal Portugal U.S.A. China Polymorphism IL-1B-511, 31 IL-1B+3954, 511 IL-1B-511 TNF-alfa-308 IL-1B-511 IL-1B-511 IL-1B-31, 511, +3954 IL-1B-511, 31, +3954 Case-controls Chang YW., 2005 Hartland S., 2005 El-Omar EM., 2003 Figueiredo C., 2002 Machado JC., 2001 El-Omar EM., 2000 Cohorts Zeng ZR., 2003 Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

19. Studies characteristics Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

20. Pooled statistics • IL-1 polymorphisms • Comparison: Gastric Cancer IL-1: Normal Vs Cancer • Outcome: Non carriers Vs Carriers Forest Plot obtained by Revman software Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

21. Pooled statistics Forest Plot obtained by Revman software Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

22. Pooled statistics Funnel Plot Funnel Plot obtained by Revman software Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

23. Pooled statistics • Outcome: Homozygous dominant allele carriers vs Homozygous variant allele carriers Forest Plot obtained by Revman software Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

24. Pooled statistics • TNF-alfa polimorphism • Comparison: Gastric Cancer TNF-alfa: Normal Vs Cancer • Outcome: Non carriers Vs Carriers Forest Plot obtained by Revman software • Outcome: Homozygous dominant allele carriers vs Homozygous variant allele carriers Forest Plot obtained by Revman software Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

25. Conclusion • Although some individual studies did not achieve statistically significant results, our pooled measures showed a relation between polymorphisms and gastric cancer. • This fact attests the importance of meta-analysis as a method of analyzing a great number of patients and compiling results from different and small studies. • The lack of significant outcomes may be explained by the small number of cohort studies. Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

26. Conclusion • Based on our studies about TNF-alfa we concluded that being a carrier or homozygous for this polymorphism may offer a protective effect against stomach cancer. • For the IL-1B-31 polymorphism, being a carrier or homozygous means having increased risk for cancer. • Polymorphisms IL-1B-511 and IL-1B+3954 increase the risk of gastric cancer, if the individual is homozygous. If the individual have only one allele, these polymorphisms have a protective effect. Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

27. Gantt Chart Web site Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

28. Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

29. References • Aviva Petrie, Caroline Sabim. Medical statistics at a Glance.2005 Blackwell Science • Burmester, G. K.; Pezzutto,Color Atlas of Immunology,2003 • Designing Clinical Research, 2nd ed. – Hulley SB, Cummings SR, Browner WS, Grady D, Hearst N, Newman TB. Lippincott Williams & Wilkins. 2001. • Pai M, McCulloch M, Gorman J, Pai N, Enanoria W, Kennedy G, Tharyan P, Colford J. Systematic reviews and meta-analyses: Ana illustrated, step-by-step guide. Nat Med J India 2004;17:86-95 On-line research • http://esynopsis.uchc.edu/eAtlas/Images/GI/7278b.gif • http://familydoctor.org/817.xml •  http://health.gov.mt/ministry/dhi/publications/mncr/stomach.htm •  http://images.google.pt •  http://info.cancerresearchuk.org • http://medlib.med.utah.edu/WebPath/jpeg4/GI139.jpg • http://www.cancer.gov/cancerinfo/wyntk/stomach • http://www.emedicine.com/med/images/1531BARRET.JPG • http://www.fmed.ulaval.cag • http://www.geocities.com/sampyroy2002/gd3.jpg • http://www.murrasaca.com/canceres3.jpg • http://www.nlm.nih.gov/ • http://www.nlm.nih.gov/medlineplus/stomachcancer.html • http://www.wrongdiagnosis.com/s/stomach_cancer/stats.htm Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

30. References [1] Pereira C., et al.,765G > C COX-2 polymorphism may be a susceptibility marker for gastric adenocarcinoma in patients with atrophy or intestinal metaplasia, World J Gastroenterol, 2006 Sep 14.12(34): p. 5473-8 [2] Starzynska T., et al., The association between the interleukin-1 polymorphisms and gastric cancer risk depends on the family history of gastric carcinoma in the study population, Am J Gastroenterol, 2006 Feb. 101(2): p. 248-54 [3] Hellmig S., et al., A functional promotor polymorphism of TNF-alpha is associated with primary gastric B-Cell lymphoma, Am J Gastroenterol, 2005 Dec. 100(12): p. 2644-9 [4] Palli D., et al., Interleukin-1 gene polymorphisms and gastric cancer risk in a high-risk Italian population, Am J Gastroenterol, 2005 Sep. 100(9): p. 1941-8 [5] Perri F., et al., Cytokine gene polymorphisms in gastric cancer patients from two Italian areas at high and low cancer prevalence, Cytokine, 2005 Jun 7. 30(5): p. 293-302 [6] Hartland S., et al., A functional polymorphism in the interleukin-1 receptor-1 gene is associated with increased risk of Helicobacter pylori infection but not with gastric cancer, Dig Dis Sci, 2004 Sep. 49(9): p. 1545-50 [7] Figueiredo C., et al., Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma, J Natl Cancer Inst, 2002 Nov 20. 94(22): p.1680-7 [8] Machado JC., et al., Interleukin 1B and interleukin 1RN polymorphisms are associated with increased risk of gastric carcinoma, Gastroenterology, 2001 Oct.121(4): p. 823-9 [9] Ikehara SK., et al., A polymorphism of C-to-T substitution at -31 IL1B is associated with the risk of advanced gastric adenocarcinoma in a Japanese population, J Hum Genet, 2006. 51(11): p. 927-33 [10] Zhang WH., et al., Association of interleukin-1B (IL-1B) gene polymorphisms with risk of gastric cancer in Chinese population, Cytokine, 2005 Jun 21. 30(6): p. 378-81 [11] Lu W., et al., Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population, Carcinogenesis, 2005 Mar. 26(3): p. 631-6 [12] Chang YW., et al., Interleukin-1B (IL-1B) polymorphisms and gastric mucosal levels of IL-1beta cytokine in Korean patients with gastric cancer, Int J Cancer, 2005 Apr 10. 114(3): p. 465-71 [13] Zeng ZR., et al., Association of interleukin 1B gene polymorphism and gastric cancers in high and low prevalence regions in China, Gut, 2003 Dec. 52(12): p. 1684-9 [14] El-Omar EM., et al., Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms, Gastroenterology, 2003 May. 124(5): p. 1193-201 [15] El-Omar EM., et al., Interleukin-1 polymorphisms associated with increased risk of gastric cancer, Nature, 2000 Mar 23. 404(6776): p.398-402 Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review

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