Molecular Genetics of HNPCC

该提案的总体目标是建立和扩大我们独特的遗传性非息肉病性结直肠癌（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例hMSH 2或hMLH 1基因携带生殖系突变的受试者的流行病学数据。 假设在癌症风险中起次要作用的基因，修饰基因，在预测HNPCC中结直肠癌的风险中是重要的。 将研究细胞周期基因如细胞周期蛋白D1、p53和p21的多态性，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因素，以确定它们是否与HNPCC的风险相关。 将研究代谢基因如N-乙酰转移酶1（NAT 1）、N-乙酰转移酶2（NAT 2）、谷胱甘肽S-转移酶M1（GSTM 1）、谷胱甘肽S-转移酶T1（GSTT 1）的多态性，以确定它们是否影响HNPCC的发病年龄，然后确定四个基因中的任何一个，结合饮食摄入数据（重点是杂环胺）影响HNPCC发病年龄。 将研究亚甲基四氢叶酸还原酶（MTHFR）基因密码子677的多态性，以确定其是否影响HNPCC的发病年龄，然后结合膳食摄入数据（重点是叶酸）确定其是否影响HNPCC的发病年龄。 将开发模型以预测i）具有MMR突变的个体将发展特定癌症的风险和ii）CRC患者将具有MMR突变的概率，给定发病年龄、MSI状态（已知）和家族史。 对于第一种类型的模型，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和回归树（CART）。这将是第一次大规模系统研究修饰基因在HNPCC中的作用。 拟议的研究将提供重要的信息，潜在的遗传和表观遗传因素参与大肠癌的HNPCC，并有可能提供新的见解的分子途径，可能会影响这一进程。

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.