Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 134, Issue 1, Pages 92-101Publisher
WILEY
DOI: 10.1002/ijc.28357
Keywords
gastric cancer; genetic susceptibility; Helicobacter pylori; NOD2; CD14
Categories
Funding
- Fundacio LaCaixa [BM06-130-0]
- Health Research Fund of the Spanish Ministry of Health [PI070130, PI081420]
- European Commission FP5, ECNIS Network of Excellence of the 6th EU Framework Programme [QLG1-CT-2001-01049, FOOD-CT-2005-513 943]
- Spanish Ministry of Health network RTICCC [ISCIII RD06/0020/0091, RD12/0036/0018]
- AGAUR, Generalitat de Catalunya [2009SGR939]
- Instituto de Salud Carlos III of the National Health System [CA06/0200]
- Europe Against Cancer Programme of the European Commission (SANCO)
- Ligue contre le Cancer (France)
- Societe 3M (France)
- Mutuelle Generale de l'Education Nationale
- Institut National de la Sante et de la Recherche Medicale (INSERM)
- German Cancer Aid
- German Cancer Research Center
- German Federal Ministry of Education and Research
- Danish Cancer Society
- Cancer Research UK
- Medical Research Council, UK
- Stroke Association, UK
- British Heart Foundation
- Department of Health, UK
- Food Standards Agency, UK
- Wellcome Trust, UK
- Hellenic Ministry of Health and Social Solidarity
- Stavros Niarchos Foundation
- Hellenic Health
- Italian Association for Research on Cancer
- Italian National Research Council
- Dutch Ministry of Public Health, Welfare and Sports
- Dutch Ministry of Health
- Dutch Prevention Funds
- LK Research Funds
- Dutch ZON (Zorg Onderzoek Nederland)
- World Cancer Research Fund (WCRF)
- Swedish Cancer Society
- Swedish Scientific Council
- Regional Government of Skane, Sweden
- Norwegian Cancer Society
- Research Institute of Bellvitge
- IDIBELL
- Cancer Research UK [14136, 16491] Funding Source: researchfish
- Medical Research Council [G0401527, G1000143] Funding Source: researchfish
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Helicobacter pylori is a recognized causal factor of noncardia gastric cancer (GC). Lipopolysaccharide and peptidoglycan of this bacterium are recognized by CD14, TLR4 and NOD2 human proteins, while NFKB1 activates the transcription of pro-inflammatory cytokines to elicit an immune response. Single nucleotide polymorphisms (SNPs) in these genes have been associated with GC in different populations. We genotyped 30 SNPs of these genes, in 365 gastric adenocarcinomas and 1,284 matched controls from the European Prospective Investigation into Cancer cohort. The association with GC and its histological and anatomical subtypes was analyzed by logistic regression and corrected for multiple comparisons. Using a log-additive model, we found a significant association between SNPs in CD14, NOD2 and TLR4 with GC risk. However, after applying the multiple comparisons tests only the NOD2 region remained significant (p=0.009). Analysis according to anatomical subtypes revealed NOD2 and NFKB1 SNPs associated with noncardia GC and CD14 SNPs associated with cardia GC, while analysis according to histological subtypes showed that CD14 was associated with intestinal but not diffuse GC. The multiple comparisons tests confirmed the association of NOD2 with noncardia GC (p=0.0003) and CD14 with cardia GC (p=0.01). Haplotype analysis was in agreement with single SNP results for NOD2 and CD14 genes. From these results, we conclude that genetic variation in NOD2 associates with noncardia GC while variation in CD14 is associated with cardia GC. What's new? Variations in immune genes appear to play an important role in determining susceptibility to gastric cancer linked to Helicobacter pylori colonization of gastric mucosa. However, little is known about the influence of variation on anatomical localization and histological subtype of this malignancy. The results of this study first confirm that NOD2 and CD14, which encode proteins that recognize H. pylori lipopolysaccharide and peptidoglycan, are significantly associated with gastric cancer risk and second indicate that NOD2 associates with noncardia and CD14 with cardia gastric cancer. The differential effects of variation on the anatomical localization of disease warrant further investigation.
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