The long-term goal of the proposed study is to provide a scientific basis to develop efficient primary prevention strategies against infection/inflammation-related cancers. Mounting evidence suggests that a variety of infectious agents have a role in the pathogenesis of human cancers. It is estimated that 15.6 percent of the worldwide cancer incidences in 1990 can be attributed to these infectious agents, accounting for a total of 1,450,000 cases. Helicobacter pylori (HP) is ranked top among various infectious agents and represents approximately 5 percent of new cancer cases in the world. These cancers are important from a public health point of view because they are potentially preventable by antibiotics treatment or vaccination. Whereas HP infection is very common (80-90 percent) in populations with high risk for stomach cancer, it is known that only a very small fraction of the population infected with HP actually develops cancer, suggesting a role for genetic components in HP-related carcinogenesis in addition to that of environmental co-factors. This proposal will specifically focus on the 2 groups of polymorphic genes, receptors to HP lipopolysaccharide (LPS), a cell wall component, which elicits immediate proinflammatory responses, (1) CD14 (C-260T), (2) TRL4 (A896G) and (3) NOD2 (3020insC); and resultant cytokines, (4) IL-8 (T-251A), (5) MCP1 (G-2518A), (6) IL-lbeta (T-31C) and (7) TNF-alpha (G-308A). These polymorphic genes are known to be functional and have been postulated to modify host responses to HP infection. The proposed study will be designed as a spin-off study of a chemo prevention trial for gastric cancer in Venezuela, taking advantage of unique characteristics of the study population, i.e., a strikingly high (95 percent) HP infection rate and high prevalence of gastric premalignant lesions. It will utilize biological specimens and epidemiological and histopathological data collected at the baseline examination from the 2200 participants. Genomic DNA will be isolated from these specimens and tested for the polymorphic genes listed above.
The specific aim of the proposed study is to evaluate whether those genotypes or alleles of the polymorphic genes which lead to greater responses to HP infection are associated with increased risk of high-grade gastric precancerous lesions. Secondary aims include to examine histopathological correlates of these polymorphisms and to determine whether selected environmental factors modify the above associations.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA098309-02
Application #
6700821
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Starks, Vaurice
Project Start
2003-02-01
Project End
2006-01-31
Budget Start
2004-02-01
Budget End
2005-01-31
Support Year
2
Fiscal Year
2004
Total Cost
$242,561
Indirect Cost
Name
Wayne State University
Department
Pathology
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Rizzato, Cosmeri; Kato, Ikuko; Plummer, Martyn et al. (2013) Risk of advanced gastric precancerous lesions in Helicobacter pylori infected subjects is influenced by ABO blood group and cagA status. Int J Cancer 133:315-22
Rizzato, Cosmeri; Kato, Ikuko; Plummer, Martyn et al. (2013) Genetic variation in PSCA and risk of gastric advanced preneoplastic lesions and cancer in relation to Helicobacter pylori infection. PLoS One 8:e73100
Canzian, Federico; Franceschi, Silvia; Plummer, Martyn et al. (2008) Genetic polymorphisms in mediators of inflammation and gastric precancerous lesions. Eur J Cancer Prev 17:178-83
Plummer, Martyn; van Doorn, Leen-Jan; Franceschi, Silvia et al. (2007) Helicobacter pylori cytotoxin-associated genotype and gastric precancerous lesions. J Natl Cancer Inst 99:1328-34
Kato, Ikuko; Canzian, Federico; Plummer, Martyn et al. (2007) Polymorphisms in genes related to bacterial lipopolysaccharide/peptidoglycan signaling and gastric precancerous lesions in a population at high risk for gastric cancer. Dig Dis Sci 52:254-61
Kato, Ikuko; van Doorn, Leen-Jan; Canzian, Federico et al. (2006) Host-bacterial interaction in the development of gastric precancerous lesions in a high risk population for gastric cancer in Venezuela. Int J Cancer 119:1666-71
Kato, Ikuko; Canzian, Federico; Franceschi, Silvia et al. (2006) Genetic polymorphisms in anti-inflammatory cytokine signaling and the prevalence of gastric precancerous lesions in Venezuela. Cancer Causes Control 17:1183-91
Lu, Yanhui; Gioia-Patricola, Lydie; Gomez, Jorge Vivas et al. (2005) Use of whole genome amplification to rescue DNA from plasma samples. Biotechniques 39:511-5
Kato, Ikuko; Vivas, Jorge; Plummer, Martyn et al. (2004) Environmental factors in Helicobacter pylori-related gastric precancerous lesions in Venezuela. Cancer Epidemiol Biomarkers Prev 13:468-76