Molecular Genetics of HNPCC

本提案的总体目标是建立和扩大我们独特的遗传性非息肉性结直肠癌（HNPCC）患者的临床和标本资源，以进一步阐明与HNPCC风险增加相关的遗传和表观遗传因素。将获得400名携带hMSH2或hMLH1基因种系突变的受试者的流行病学数据。我们推测，在癌症风险中起次要作用的基因，即修饰基因，在预测HNPCC患者结直肠癌风险中起重要作用。细胞周期基因如细胞周期蛋白D1、p53和p21的多态性将被研究，以确定它们是否影响HNPCC的发病年龄。将研究环境因素，特别是涉及叶酸途径和杂环胺摄入的环境因素，以确定它们是否与HNPCC的风险相关。研究代谢基因如N-乙酰转移酶1 （NAT1）、N-乙酰转移酶2 （NAT2）、谷胱甘肽s -转移酶M1 （GSTM1）、谷胱甘肽s -转移酶T1 （GSTT1）的多态性，以确定它们是否影响HNPCC的发病年龄，然后确定这四种基因中的任何一种，结合饮食摄入数据（重点是杂环胺）影响HNPCC的发病年龄。将研究密码子677处亚甲基四氢叶酸还原酶（MTHFR）基因的多态性，以确定它是否影响HNPCC的发病年龄，然后结合饮食摄入数据（重点是叶酸）确定它是否影响HNPCC的发病年龄。将建立模型来预测i) MMR突变个体发展为特定癌症的风险；ii)考虑到发病年龄、MSI状态（已知的）和家族史，CRC患者发生MMR突变的概率。对于第一种模型，我们将使用新开发的亲属队列方法。为了预测个体是突变携带者的概率，我们将应用逻辑回归和分类回归树（CART）。这将是第一个关于修饰基因在HNPCC中作用的大型系统研究。拟议的研究将提供有关HNPCC中参与结直肠癌发生的潜在遗传和表观遗传因素的重要信息，并有可能为可能影响这一过程的分子途径提供新的见解。

The overall goal of this proposal is to build upon and expand our unique clinical and specimen resource of hereditary non-polyposis colorectal cancer (HNPCC) patients to further elucidate genetic and epigenetic factors associated with increased risk for HNPCC. Epidemiologic data will be obtained on 400 subjects carrying germline mutations in either the hMSH2 or hMLH1 gene. It is hypothesized that genes playing minor roles in risk of cancer, modifier genes, are important in predicting risk of colorectal cancer in HNPCC. Polymorphisms in cell cycle genes such as cyclin D1, p53, and p21, will be studied to determine if they influence age of onset in HNPCC. Environmental factors, particularly those involving the folate pathway and heterocyclic amines intake will be studied to determine if they are associated with risk of HNPCC. Polymorphisms in metabolic genes such as N- Acetyltransferase 1 (NAT1), N-Acetyltransferase 2 (NAT2), Glutathione S-transferase M1 (GSTM1), Glutathione S-transferase T1 (GSTT1), will be studied to determine if they influence age of onset of HNPCC, and then to determine if any of the four genes, in combination with dietary intake data (with emphasis on heterocyclic amines) influence age of onset in HNPCC. A polymorphism of the Methylene tetrahydrofolate reductase (MTHFR) gene at codon 677 will be studied to determine if it influences age of onset of HNPCC, and then to determine in combination with dietary intake data (with emphasis on folate) if it influence age of onset of HNPCC. Models will be developed to predict i) the risk that an individual with MMR mutation will develop specific cancers and ii) the probability that a CRC patient will have a MMR mutation given the age at onset, MSI status (where known), and family history. For the first type of model, we will use the newly developed kin-cohort approach. To predict the probability that an individual is a mutation carrier, we will apply logistic regression and Classification and Regression Trees (CART). This will be the first large systematic study on the roles of modifier genes in HNPCC. The proposed studies will provide important information regarding underlying genetic and epigenetic factors involved in colorectal carcinogenesis in HNPCC and has the potential to provide novel insights into the molecular pathways that might influence this process.