Molecular Epidemiology of Colorectal Cancer

描述（由申请人提供）：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，旨在研究基因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。结直肠癌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。结直肠癌的流行病学危险因素已经得到了很好的描述，然而大多数结直肠癌发生在除了年龄较大之外没有已知危险因素的个体中。低外显率易感等位基因，如APC 11307K，可能在这种复杂疾病的群体动态中发挥重要作用，但导致结直肠癌的遗传变异在很大程度上尚未被探索。因此，MECC研究的广泛目标是了解经典流行病学因素和遗传变异如何与CRC的风险、发病机制和预后相关。以色列有明确的人口结构，这有利于基因发现，以色列不同人群中结直肠癌发病率的差异为研究环境和遗传对结直肠癌的影响提供了流行病学背景。在这项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合作研究中，我们计划评估两个假设：1)临床特征、体细胞分子标记和肿瘤表达谱预测无复发生存、疾病特异性生存和总生存；2)以前未被识别的基因与结直肠癌的风险有关，可以使用全基因组关联来识别。这些假设将通过以下具体目标进行评估：1)利用临床、实验室和流行病学数据，结合快速冷冻肿瘤的表达谱，发现MECC病例CRC复发和生存的新预后因素；2)使用40万个精心挑选的单核苷酸多态性（snp）完成CRC的全基因组关联研究，这些snp密集分布在所有已知人类基因的85%左右。

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.