Molecular Epidemiology of Colorectal Cancer Subtypes

描述(申请人提供)：结直肠癌(CRC)是美国第三大恶性死亡原因。尽管环境因素似乎在调节结直肠癌风险方面很重要，但与大多数疾病修饰性暴露因素相关的细胞内事件仍未完全确定。少数回顾研究表明，某些环境因素，特别是那些可能直接或间接影响一碳代谢所涉及的相互关联的生化反应网络的因素，可能与结直肠癌发生的替代途径有关。在目前的应用中，我们建议在一项基于人群的队列研究中检查散发性CRC亚型的分子流行病学。我们的具体目的是研究吸烟、雌激素暴露和叶酸摄入与由微卫星不稳定表型、Ki-ras或p53基因突变和CpG岛甲基化表型定义的不同的CRC亚型之间的关系。随着新数据的出现，为该项目产生的组织资源也将促进未来对其他候选暴露的高成本效率的分析，以支持与特定的遗传/表观遗传致癌机制的潜在关联。因此，PI(新的调查员)应该能够从当前的应用程序中获得更多的好处并表现出非凡的生产力。本研究陈述的具体目标的实现将利用爱荷华州妇女健康研究队列的数据和组织资源。石蜡包埋的组织样本将从1991至2000年间被诊断为偶发癌的受试者身上采集。DNA将被提取用于遗传和表观遗传分析，显微镜载玻片将被切割用于免疫组织化学染色。到目前为止，还没有关于分子定义的结直肠癌风险关联的前瞻性数据报道。按照设计，拟议的研究涉及由NCI赞助的CRC进度审查小组确定的一个研究优先领域，并与最近NCI计划公告(PA-04-099)的目标一致。该项目的成功完成将产生关于受常见暴露因素影响的结直肠癌致癌途径的新的、信息丰富的数据。将散发性癌分类为分子定义的亚型可能是有益的，因为增加的肿瘤同质性应该允许对潜在的病因风险关联进行更准确的评估。对散发性结直肠癌分子流行病学的进一步研究也将有助于开发更精确的致病模型，这可能会在多个水平上培育新的干预策略，包括风险分层、早期发现、行为改变、化学预防和/或化疗。

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is the third leading cause of malignant death in the United States. Although environmental factors appear to be important in modulating CRC risk, the intracellular events associated with most disease-modifying exposure agents remain incompletely defined. Observations from a small number of retrospective studies suggest that some environmental factors, particularly those which might directly or indirectly influence the interrelated network of biochemical reactions involved in one-carbon metabolism, may be associated with alternate pathways of colorectal carcinogenesis. In the present application, we propose to examine the molecular epidemiology of sporadic CRC subtypes in a population-based cohort study. Our specific aims are to examine associations between cigarette smoking, estrogen exposure, and folate intake with distinct CRC subtypes defined by microsatellite instability phenotype, Ki-ras or p53 gene mutations, and CpG island methylator phenotype. The tissue resources generated for this project will also facilitate future, highly cost-efficient, analyses of other candidate exposures as new data emerge to support potential associations with specific genetic/epigenetic mechanisms of carcinogenesis. Thus, the PI (new investigator) should be able to derive extended benefits and demonstrate exceptional productivity from the current application. Achievement of the stated specific aims for our present study will capitalize upon data and tissue resources from the Iowa Women's Health Study cohort. Paraffin-embedded tissue samples will be collected from subjects who were diagnosed with incident CRCs between 1991and 2000. DNA will be extracted for genetic and epigenetic analyses and microscopy slides will be cut for immunohistochemical staining. To date, no prospective data have been reported regarding molecularly defined CRC risk associations. As designed, the proposed study addresses a research priority area identified by the NCI sponsored CRC Progress Review Group and is consistent with the objectives of a recent NCI Program Announcement (PA-04-099). Successful completion of this project should yield novel, informative data regarding the colorectal carcinogenic pathways influenced by common exposure agents. Categorization of sporadic CRCs into molecularly-defined subtypes is likely to be rewarding, because the increased tumor homogeneity should permit more accurate assessment of potentially etiologic risk associations. Further investigation of the molecular epidemiology of sporadic CRC should also permit the development of more precise pathogenic models for this disease, which may foster novel intervention strategies at multiple levels, including risk stratification, early detection, behavioral modification, chemoprevention, and/or chemotherapy.