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Polymorphisms of Inflammatory Genes and Gastric Cancer: A
Systematic Review
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
Introduction to Medicine 2006/2007
http://www.nlm.nih.gov/
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Stomach cancer incidence Stomach cancer incidence ratesrates
- By sex (Europe)
http://health.gov.mt/ministry/dhi/publications/mncr/stomach.htm
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Stomach cancer Survival Stomach cancer Survival ratesrates
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
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CancerCancerDisease 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 CancerStomach CancerStomach 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
Polymorphisms of Inflammatory Genes Gastric Cancer
http://www.cancer.gov/cancerinfo/wyntk/stomachhttp://www.nlm.nih.gov/medlineplus/stomachcancer.html
Risk factor?
Protective factor?
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Epidemiological studies show a clear association between chronic inflammatory conditions and subsequent malignant transformation in the inflamed tissue.
Polymorphisms of Inflammatory Polymorphisms of Inflammatory Genes as a gastric cancer’s Genes as a gastric cancer’s causecause
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/
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Proinflammatory cytokine gene polymorphisms may increase or reduce the risk of cancer and its precursors.
Polymorphisms of Inflammatory Polymorphisms of Inflammatory Genes as a gastric cancer’s Genes as a gastric cancer’s causecause
IL-1IL-1ββ, IL-6, TNF-TNF-αα, CXCL,
CCR, COX-2COX-2
Burmester, G. K.; Pezzutto,Color Atlas of Immunology,2003
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
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Aim:Aim:
To perform a systematic review of studies on risk of gastric To perform a systematic review of studies on risk of gastric cancer associated with genetic polymorphisms related with cancer associated with genetic polymorphisms related with Cox, TNF and IL-1.Cox, TNF and IL-1.
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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MethodsMethods
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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StudyStudy designdesign
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
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• Inclusion Criteria:Inclusion Criteria:
Original articles, observational studies, that evaluated the risk of gastric cancer according to Polymorphisms of Inflammatory Genes
• Exclusion Criteria:Exclusion Criteria:
Case Reports Case series Reviews Language (we only accept articles written in English
or French)
Study designStudy design
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Flow Chart – First StageFlow Chart – First StageStart
NoYes
Fullfil the inclusion criteria?
Yes
No
32 articles excluded
Read titles and abstractsN=48
3 articles had no abstract
Read titles and abstractsN=83
Obtain full articlesN=3
Read full articlesN=3
Identify adequate databases
Perform bibliographic research on MedLine
Define a Query
48 articles included
I ncluded by two reviewers?
Read by a third reviewer
Include article?
Yes
No
35 abstracts excluded
(Not related with the theme)
19 articles included
Search for full articles in MedLine and Scopus
19 articles found
86 articles found
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Flow Chart – Second StageFlow Chart – Second Stage19 articles found
Select full articles according to inclusion and exclusion criteria
I ncluded by two reviewers?
Read by a third reviewer
Yes No
Include article?
Yes
15 articles included
No
4 articles excluded
Extract Data(2 reviewers)
I nsert and analyse data using SPSS and RevMan
Discuss and interprete the results
Identify limitations of the review
Write the report
End
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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ResultsResults
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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SELECTION BIASSELECTION BIAS1. 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 BIASPERFORMANCE BIAS4. 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 BIASATTRITION BIAS6. Was follow up sufficiently complete (at least
80%)?
DETECTION BIASDETECTION BIAS7. Were the outcomes measured in the same way in the groups being compared?
Quality criteriaQuality criteria
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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AuthorType of Study
Blinding of
outcome
assesors
Elimination of
confounders
Adjustment for
differences
Unawareness of the assigned
intervention
Identifica-tion of the groups
Follow-up
complete
Similarity in
measuring the
outcomes
Pereira C.
CC Y Y Y Y Y - Y
Ikehara SK.
CC Y N N N Y - Y
Starzynska T.
CC Y Y Y Y Y - Y
Hellmig S. CC Y Y Y Y Y - Y
Palli D. CC Y Y Y Y Y - Y
Perri F. CC Y N N N Y - Y
Zhang WH.
CC Y N N Y Y - Y
Lu W. CC Y Y Y Y Y - Y
Chang YW. CC Y Y Y Y Y - Y
Hartland S. CC Y Y Y Y Y - Y
Zeng ZR. C Y Y Y Y Y U Y
El-Omar EM. CC Y N N Y Y - Y
Figueiredo C. CC Y Y Y Y Y - N
Machado JC.
CC Y Y Y Y Y - Y
El-Omar EM. CC Y Y Y Y Y - Y
Y - Yes
N - No U - Unknown
Quality analysisQuality analysis
CC- Case-control
C - Cohort
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Quality analysisQuality analysis
Quality Criteria
012345678
Ikeh
ara
SK
.
El-O
mar
EM
.
Fig
ueire
doC
.
Sta
rzyn
ska
T.
Pal
li D
.
Cha
ng Y
W.
Mac
hado
JC.
Zen
g Z
R.
Articles
Qu
alit
y
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Studies characteristicsStudies characteristics
Case-controlsCase-controls
Pereira C., 2006Pereira C., 2006
Ikehara SK., 2006Ikehara SK., 2006
Starzynska T., Starzynska T., 20062006
Hellmig S., 2005Hellmig S., 2005
Palli D., 2005 Palli D., 2005
Perri F., 2005Perri F., 2005 Zhang WH., 2005Zhang WH., 2005
Lu W., 2005Lu W., 2005
PolymorphiPolymorphismsm
COX-2COX-2
IL-1B-31,-511IL-1B-31,-511
IL-1B-511IL-1B-511
TNF-alfa-238, TNF-alfa-238, 308, 857, 308, 857, 10311031
IL-1B-31, IL-1B-31, +3954, -511+3954, -511
TNF-alfa-308TNF-alfa-308
IL-1B-31, -IL-1B-31, -511,511, +3954+3954
IL-1B-31, 511IL-1B-31, 511TNF-alfa-308TNF-alfa-308
Local Local of of StudyStudyPortugaPortugall
JapanJapan
PolandPoland
GermanGermanyy
Italy Italy
ItalyItaly
ChinaChina
ChinaChina
% male % male gendergender(cases)(cases)4949
7373
6161
5454
5858
6060
8484
7373
% male % male gendergender(controls)(controls)6464
7373
4848
4848
4949
5353
8484
7272
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Case-controlsCase-controls
Chang YW., 2005Chang YW., 2005
Hartland S., 2005Hartland S., 2005 El-Omar EM., 2003El-Omar EM., 2003
Figueiredo C., Figueiredo C., 20022002 Machado JC., 2001Machado JC., 2001
El-Omar EM., 2000El-Omar EM., 2000 CohortsCohorts
Zeng ZR., 2003Zeng ZR., 2003
PolymorphisPolymorphismm
IL-1B-511, 31IL-1B-511, 31
IL-1B+3954, IL-1B+3954, 511511
IL-1B-511IL-1B-511TNF-alfa-308TNF-alfa-308
IL-1B-511IL-1B-511
IL-1B-511IL-1B-511
IL-1B-31, 511, IL-1B-31, 511, +3954+3954
IL-1B-511, 31, IL-1B-511, 31, +3954+3954
Local ofLocal of studystudy
S KoreaS Korea
UKUK
U.S.A.U.S.A.
PortugalPortugal
PortugalPortugal
U.S.A.U.S.A.
ChinaChina
% male % male gendergender(controls(controls))--
6868
7878
--
--
--
5858
% % male male gendegenderr(cases)(cases) --
3232
8585
--
--
--
3737
Studies characteristicsStudies characteristics
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Studies characteristicsStudies characteristics
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Pooled Pooled statisticsstatistics
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
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Forest Plot obtained by Revman software
Pooled Pooled statisticsstatistics
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Funnel Plot obtained by Revman software
Funnel Plot
Pooled Pooled statisticsstatistics
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Outcome: Homozygous dominant allele carriers vs Homozygous variant allele carriers
Pooled statistics
Forest Plot obtained by Revman software
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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TNF-alfa polimorphism
Comparison: Gastric Cancer TNF-alfa: Normal Vs Cancer Outcome: Non carriers Vs Carriers
Forest Plot obtained by Revman software
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
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ConclusionConclusion
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
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ConclusionConclusion
• Based on our studies about TNF-alfaTNF-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 IL-1B-31 polymorphism, being a carrier or homozygous means having increased risk for cancer.
• Polymorphisms IL-1B-511IL-1B-511 and IL-1B+3954IL-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
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Gantt Gantt ChartChartWeb siteWeb site
Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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Polymorphisms of Inflammatory Genes and Gastric Cancer: A Systematic Review
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ReferencesReferences
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
On-line On-line researchresearch
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
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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
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The EndThe End