GENETIC EPIDEMIOLOGIC STUDIES OF POLYPS AND CANCER

描述（改编自申请人摘要）：结直肠癌的病因学 癌症和息肉涉及遗传和环境因素。结肠 暴露于大量的遗传毒性化合物， 同族通婚的来源。遗传性非息肉病性结直肠癌说明了 DNA修复机制在结直肠癌发生中的重要性我们 假设常见DNA修复酶的多态性也可能影响 结直肠肿瘤的风险。在这项资助的前4年，我们 测量了几种多态性酶a）与特定的代谢有关， 来自饮食和烟草烟雾的致癌物和B）叶酸途径。 与酒精代谢相关的其他酶的多态性（也是酒精代谢的来源） DNA损伤）和旋转代谢与DNA修复通过提供 核苷酸）也可以调节风险。这一竞争性更新的目标是 研究结肠癌、结肠直肠腺瘤和结肠直肠癌的风险。 增生性息肉与1）DNA修复酶多态性有关， 特别是在hMLHI、hMSH2、MSH6、hOGGI、XRCC 1、XRCC 3、XPD和AGT中; 2） 与酒精代谢相关的多态性，特别是酒精 叶酸酶2、3和4;以及3）叶酸酶中的多态性 代谢，特别是在MTHFR，胸苷酸合成酶（TS）和蛋氨酸 合成酶我们计划进一步研究可能的相互作用，以确定 结直肠肿瘤的风险：1）相关环境暴露与 遗传多态性（例如，叶酸和TS多态性的膳食摄入量; 熟肉和核苷酸切除修复酶）;和2）之间 DNA修复基因和叶酸或酒精相关基因的多态性 内切酶两项关于结直肠息肉（腺瘤）的大型病例对照研究 n = 550例病例，n = 700例对照，增生性息肉，n = 200例）和结肠 癌症（n = 1650例病例，n = 1950例对照）-关于饮食、酒精的广泛数据 摄入量，吸烟史，家族史，以及基因型信息， 其他相关基因-将为这项研究提供基础。的信息 DNA损伤修复途径多态性的数量及其与 相关的曝光将有助于我们了解 结直肠肿瘤形成阶段的机制;最终， 研究结果应为未来的筛查和预防提供方向 战略布局

DESCRIPTION (Adapted from applicant's abstract): The etiology of colorectal cancer and polyps involves genetic as well as environmental factors. The colon is exposed to a large number of genotoxic compounds both from exogamous and endogamous sources. Hereditary non-polyposis colorectal cancer illustrates the importance of DNA repair mechanisms in colorectal carcinogenesis. We hypothesize that polymorphisms in common DNA repair enzymes may also affect the risk of colorectal neoplasia. In the first 4 years of this grant, we have measured several polymorphic enzymes a) related to the metabolism of specific carcinogens from diet and tobacco smoke and b) in the folate pathway. Polymorphisms in other enzymes related to alcohol metabolism (also a source of DNA damage) and rotate metabolism linked to DNA repair via the provision of nucleotides) may also modulate risk. The goals of this competing renewal are to investigate the risk of colon cancer, colorectal adenoma, and colorectal hyperplastic polyps associated with 1) polymorphisms in DNA repair enzymes, specifically in hMLHI, hMSH2, MSH6, hOGGI, XRCC1, XRCC3, XPD, and AGT; 2) polymorphisms related to alcohol metabolism, specifically alcohol dehydrogenases 2,3, and 4; and 3) polymorphisms in enzymes in folate metabolism, specifically in MTHFR, thymidylate synthase (TS), and methionine synthase. We further plan to investigate possible interactions in determining risk of colorectal neoplasia: 1) between relevant environmental exposures and genetic polymorphisms (e.g., dietary intakes of folate and TS polymorphisms; cooked meat and nucleotide-excision repair enzymes); and 2) between polymorphisms in DNA repair genes and those in folate, or alcohol-related enzymes. Two large completed case-control studies of colorectal polyps (adenoma n=550 cases, n=700 controls, and hyperplastic polyps, n=200 cases) and colon cancer (n=1650 cases, n=1950 controls) - with extensive data on diet, alcohol intake, smoking history, and family history, as well as genotype information on other relevant genes - will provide the basis for this study. Information on a number of DNA damage-repair pathway polymorphisms and their interactions with relevant exposures will help build our understanding of the molecular mechanisms involved in the stages of colorectal neoplasia; ultimately, the findings should provide directions for future screening and prevention strategies.