MTHFR POLYMORPHISMS IN PANCREATIC CANCER IN SF BAY AREA

DNA修复能力对于维持遗传完整性和正常的细胞功能以及控制异常细胞生长是必不可少的。生物合成DNA修复机制所需的寡核苷酸需要叶酸，而叶酸不足与人类癌症有关。亚甲基四氢叶酸还原酶(MTHFR)是调节叶酸和蛋氨酸代谢的关键酶。由于叶酸在DNA合成、修复和甲基化中起重要作用，它可能在癌症预防中发挥作用，最近的证据表明情况就是这样。这项研究的总体目标是确定MTHTR基因C677T和A1298C多态在胰腺癌患者和对照组之间是否存在差异。在这项大规模的基于人群的病例对照研究中，将对334名病例和966名对照参与者进行DNA检测，其中包括550名胰腺癌患者和1600名对照。所有基因测试将使用加州大学旧金山分校综合癌症中心基因组核心设施和实验室人员进行。对在大型研究中的访谈中收集的变量和MTHFR遗传部分的数据分析也将在拟议工作下完成。其具体目的是：1)确定和比较胰腺癌患者和对照组中MTHFR C677T和A1298C基因多态的发生率；2)评估MTHFR基因多态与其他可能与胰腺癌风险相关的暴露之间的关系，如饮食中的叶酸、吸烟和饮酒；以及3)对其他饮食因素和在母研究中收集的其他数据进行分析。数据将使用分层和多元Logistic回归分析所有风险因素，这些因素可能会混淆或改变MTHFR基因多态与胰腺癌之间的联系，如饮食中的叶酸、吸烟和饮酒。来自其他风险因素的数据也将被分析。虽然低血清叶酸与胰腺癌发病风险之间的关系已有报道，但尚无数据描述胰腺癌患者和对照人群中MTHFR基因的多态性。这些基于问卷和遗传学的分析将提供新的、具有挑衅性的数据，说明这种毁灭性疾病对公共卫生的重要性。

The capacity for DNA repair is essential to maintain both genetic integrity and normal cellular function and to control abnormal cell growth. Folate is required for biosynthesis of oligonucleotides needed for DNA repair mechanisms and inadequate folate has been associated with human cancer. The methylenetetrahydrofolate reductase (MTHFR) enzyme is critical in the regulation of folate and methionine metabolism. Because folate is important in DNA synthesis, repair and methylation, it may play a role in cancer prevention and recent evidence suggests that this is the case. The overall goal of this study is to determine whether the prevalence of the C677T and A1298C polymorphisms in the MTHTR gene differs between pancreatic cancer patients and control subjects. DNA will be examined from 334 cases and 966 control participants who had blood drawn in the large population-based case-control study that included 550 pancreatic cancer patients and 1600 controls. All genetic testing will be done using the UCSF Comprehensive Cancer Center Genome Core facilities and laboratory personnel. Data analyses for the variables collected in the interviews in the large study and for the MTHFR genetic component also will be completed variables collected in the interviews in the large study and for the MTHFR genetic component also will be completed under the proposed work. The specific aims are to: 1) identify and compare the incidence of MTHFR C677T and A1298C polymorphisms in pancreatic cancer patients and control subjects; 2) evaluate the relationships between MTHFR polymorphisms and other exposures that also may be related to risk for pancreatic cancer such as dietary folate, smoking and alcohol consumption; and 3) perform analyses of other dietary factors and other data collected in the parent study. Data will be analyzed using stratification and multiple logistic regression for all risk factors that could potentially confound or modify the association between the MTHFR polymorphisms and pancreatic cancer such as dietary folate, smoking and alcohol consumption. Data from other risk factors also will be analyzed. While a relationship between low serum folate and risk for pancreatic has been reported there is no data to describe polymorphisms in MTHFR genes among pancreatic cancer patients and control subjects. These questionnaire- and genetics-based analyses will provide new and provocative data of public health importance for this devastating disease.