Genetic Susceptibility to Infection Related Cancer

描述（由申请人提供）：拟议研究的长期目标是为制定针对感染/炎症相关癌症的有效一级预防策略提供科学依据。越来越多的证据表明，多种感染因子在人类癌症的发病机制中起作用。据估计，1990年全世界15.6%的癌症发病率可归因于这些传染因子，总共有145万例。幽门螺杆菌（HP）在各种感染因子中排名第一，约占世界新发癌症病例的5%。从公共卫生的角度来看，这些癌症很重要，因为它们有可能通过抗生素治疗或接种疫苗来预防。尽管HP感染在胃癌高危人群中非常常见（80- 90%），但已知只有很小一部分感染HP的人群实际发展为癌症，这表明除了环境辅助因素外，遗传成分在HP相关的致癌作用中也起着作用。该提案将特别关注两组多态性基因，即HP脂多糖（LPS）的受体，一种细胞壁成分，可引起立即的促炎反应，(1)CD14 (C-260T), (2) TRL4 （A896G）和(3)NOD2 (3020insC)；以及由此产生的细胞因子，(4)IL-8 (T-251A), (5) MCP1 (G-2518A), (6) il - β (T-31C)和(7)tnf - α (G-308A)。这些多态基因已知是功能性的，并被认为可以改变宿主对HP感染的反应。拟议的研究将被设计为委内瑞拉胃癌化疗预防试验的衍生研究，利用研究人群的独特特征，即惊人的高（95%）HP感染率和高患病率的胃癌前病变。它将利用从2200名参与者的基线检查中收集的生物标本和流行病学和组织病理学数据。基因组DNA将从这些标本中分离出来，并测试上面列出的多态性基因。该研究的具体目的是评估那些导致对HP感染产生更大反应的多态基因的基因型或等位基因是否与高级别胃癌前病变风险增加有关。次要目的包括检查这些多态性的组织病理学相关性，并确定选定的环境因素是否改变上述关联。

DESCRIPTION (provided by applicant): 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.