Molecular Epidemiology of Colorectal Cancer

描述（由申请方提供）：结直肠癌分子流行病学（MECC）研究是一项基于人群的病例对照研究，旨在研究遗传序列变异和环境因素对结直肠癌（CRC）风险、发病机制和预后的影响。CRC是美国癌症死亡的第二大原因，也是以色列癌症死亡的主要原因。CRC的流行病学危险因素得到了合理的描述，但大多数CRC发生在除老年外没有已知危险因素的个体中。低等位基因易感性等位基因，如APC 11307 K可能在这种复杂疾病的群体动态中发挥重要作用，但导致CRC的遗传变异在很大程度上尚未探索。因此，MECC研究的主要目的是了解经典流行病学因素和遗传变异与CRC的风险、发病机制和预后的关系。以色列有一个明确的人口结构，有利于基因的发现，在以色列不同人群之间的CRC发病率的差异提供了一个流行病学背景下，研究环境和遗传因素对CRC的贡献。在密歇根大学和以色列海法卡梅尔医学中心国家癌症控制中心的这项合作研究中，我们计划评估2个假设：1）临床特征、体细胞分子标志物和肿瘤表达谱预测无复发生存期、疾病特异性生存期和总生存期，2）以前未被识别的基因有助于结直肠癌的风险，可以使用全基因组关联来识别。将通过以下具体目标对这些假设进行评价：1）使用临床、实验室和流行病学数据结合速冻肿瘤的表达谱，发现MECC病例的CRC复发和存活的新预后因素，以及2）使用400，000个精心挑选的单核苷酸多态性（SNP），这些SNP密集分布在所有已知人类基因的约85%中。

DESCRIPTION (provided by applicant): The Molecular Epidemiology of Colorectal Cancer (MECC) study is a population-based case-control study that examines the contribution of genetic sequence variation and environmental factors to the risk, pathogenesis, and prognosis of colorectal cancer (CRC). CRC is the second leading cause of cancer death in the United States and the leading cause of cancer death in Israel. Epidemiologic risk factors for CRC are reasonably well described, yet the majority of CRC arises in individuals with no known risk factors other than older age. Low penetrance susceptibility alleles such as APC 11307K are likely to play an important role in the population dynamics of this complex disease, yet the genetic variation that contributes to CRC is largely unexplored. Thus the broad objective of the MECC study is to understand how classic epidemiologic factors and genetic variation are related to the risk, pathogenesis, and prognosis of CRC. Israel has a well-defined population structure that facilitates gene discovery, and the differences in the incidence of CRC among different populations within Israel provide an epidemiologic context to study environmental and genetic contributions to CRC. In this collaborative study between the University of Michigan and the National Center for Cancer Control at Carmel Medical Center in Haifa, Israel we plan to evaluate 2 hypotheses: 1) Clinical features, somatic molecular markers, and tumor expression profiles predict relapse-free survival, disease-specific survival, and overall survival, 2) Previously unrecognized genes contribute to the risk of colorectal cancer and can be identified using a whole genome association. These hypotheses will be evaluated through the following specific aims: 1) Discover novel prognostic factors for CRC recurrence and survival of the MECC cases using clinical, laboratory, and epidemiologic data in conjunction with expression profiles of snap frozen tumors, and 2) Complete a whole genome association study of CRC using 400,000 carefully selected single nucleotide polymorphism (SNPs) that are densely spaced in and around approximately 85% of all known human genes.