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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
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
2
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.cancerresearc
huk.org
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
3
Cancer Cancer
Stomach
Stomachin
Disease
cancer
whichis the
the body's
growthcells
of cancer
become
cellsabnormal
in the lining
and and
divide
wallwithout
of the
control.
stomach.
Cancer
may are
invade
nearby
theyover
maymany
spread
through the
Stomachcells
cancers
believed
to tissues
developand
slowly
years.
bloodstream and lymphatic system to other parts of the body.
MEN / WOMEN
Polymorphisms of
Inflammatory Genes
ENVIRONMENT
Risk factor?
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
4
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
5
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.
Burmester, G. K.; Pezzutto,Color Atlas of Immunology,2003
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
6
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
7
Methods
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
8
Study design

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
9
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
10
Flow Chart – First Stage
Start
Identify adequate databases
Define a Query
Perform bibliographic research on MedLine
86 articles found
3 articles had no abstract
Obtain full articles
N=3
Read titles and abstracts
N=83
Included by two
reviewers?
Yes
No
Read by a third
reviewer
48 articles included
Yes
Include
article?
Read full articles
N=3
No
Read titles and abstracts
N=48
35 abstracts
excluded
(Not related
with the theme)
Fullfil the inclusion
criteria?
No
32 articles
excluded
Yes
19 articles
included
Search for full articles in
MedLine and Scopus
19 articles found
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
11
Flow Chart – Second Stage
19 articles found
Select full articles according to
inclusion and exclusion criteria
Included by two
reviewers?
Yes
No
Read by a third
reviewer
15 articles
included
Yes
Include
article?
Extract Data
(2 reviewers)
No
4 articles
excluded
Insert 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
12
Results
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
13
Quality criteria
SELECTION BIAS
1. Did the investigators do any type of blinding?
2.Did the investigators demonstrate similarity
determinants of outcome?
3. Did they adjust for differences in the analysis?
in
all
known
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
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Quality analysis
Author
Type 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
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
Zeng ZR.
U - Unknown
CC- Case-control
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
C - Cohort
15
Quality analysis
Zeng ZR.
Machado
JC.
Chang YW.
Palli D.
Starzynska
T.
Figueiredo
C.
El-Omar
EM.
8
7
6
5
4
3
2
1
0
Ikehara SK.
Quality
Quality Criteria
Articles
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
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Studies characteristics
Polymorphism
Case-controls
Pereira C., 2006
COX-2
Local of
Study
Portugal
Ikehara SK., 2006
IL-1B-31,-511
Japan
Starzynska T., 2006
IL-1B-511
Poland
Hellmig S., 2005
TNF-alfa-238,
308, 857, 1031
Germany
Palli D., 2005
IL-1B-31,
+3954, -511
Italy
Perri F., 2005
TNF-alfa-308
Italy
Zhang WH., 2005
IL-1B-31, -511,
+3954
China
Lu W., 2005
IL-1B-31, 511
TNF-alfa-308
China
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
% male
gender
(cases)
49
% male
gender
(controls)
64
73
73
61
48
54
48
58
49
60
53
84
84
73
72
17
Studies characteristics
% male
gender
(cases)
-
% male
gender
(controls)
-
Polymorphism
Local of
study
Chang YW., 2005
IL-1B-511, 31
S Korea
Hartland S., 2005
IL-1B+3954, 511 UK
32
68
El-Omar EM., 2003
IL-1B-511
TNF-alfa-308
U.S.A.
85
78
Figueiredo C., 2002 IL-1B-511
Portugal
-
-
Machado JC., 2001
IL-1B-511
Portugal
-
-
El-Omar EM., 2000
IL-1B-31, 511,
+3954
U.S.A.
-
-
IL-1B-511, 31,
+3954
China
37
58
Case-controls
Cohorts
Zeng ZR., 2003
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
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Studies characteristics
Individuals Median Age
Number of Studies
7
6
5
4
Controls Median Age
3
Patients Median Age
2
1
0
[20-24]
[25-29]
[30-34]
[35-39]
[40-44]
[45-49]
[50-54]
[55-59]
[60-64]
[65-69]
Age Interval
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
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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
20
Pooled statistics
Forest Plot obtained by Revman software
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
21
Pooled statistics
Funnel Plot
Funnel Plot obtained by Revman software
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
22
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
23
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
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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
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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
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Gantt Chart
Web 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
28
References
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 Burmester, G. K.; Pezzutto,Color Atlas of Immunology,2003
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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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http://esynopsis.uchc.edu/eAtlas/Images/GI/7278b.gif
http://familydoctor.org/817.xml
http://health.gov.mt/ministry/dhi/publications/mncr/stomach.htm
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http://medlib.med.utah.edu/WebPath/jpeg4/GI139.jpg
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Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
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References
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with atrophy or intestinal metaplasia, World J Gastroenterol, 2006 Sep 14.12(34): p. 5473-8
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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
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[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
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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
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[14] El-Omar EM., et al., Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene
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Polymorphisms of Inflammatory Genes and
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Gastric Cancer: A Systematic Review
The End
Polymorphisms of Inflammatory Genes and
Gastric Cancer: A Systematic Review
31