Prostate cancer and genes of the one-carbon cycle

描述(申请人提供)：前列腺癌是最常见的癌症，也是美国男性癌症相关死亡的第二大原因。然而，人们对前列腺癌的病因和晚期疾病的风险因素知之甚少。最近，可能改变DNA甲基化模式的饮食影响被认为与各种癌症的病因有关。然而，很少有研究人员研究DNA甲基化与可能与前列腺癌相关的基因类型之间的关系。本研究的目的是探讨通过叶酸代谢途径影响DNA甲基化的主要基因与前列腺癌之间的潜在关系。我们假设(1)生物和环境因素都影响散发性前列腺癌的发病，以及(2)这些因素的种族/文化差异可能解释疾病类型的种族差异。这项研究的总体目标是使用新的分析方法来确定在不同人群中选择的一碳代谢基因的常见变异是否会改变散发性前列腺癌的风险。相关性的存在可能有助于确定疾病进展的过程，以及最有可能患前列腺癌和进展最快的个人。叶酸对前列腺癌发生的影响可能涉及多个基因位点和环境暴露的相互作用。因此，在精心设计的流行病学研究的背景下同时考虑多个预测因素是重要的。本研究拟研究的基因包括MTHFR、CBS、MS、MSRR、TS和SHMT。将探索新的分析方法，包括CART、单倍型分析、修剪和加权。目前正在进行的一项由医院资助的病例对照研究设计将用于实现以下三个具体目标：(1)按种族/民族确定与叶酸代谢相关的基因类型的频率；(2)确定前列腺癌与与单碳代谢相关的基因类型之间的关联；(3)确定叶酸摄入量和基因对前列腺癌发生和发展的影响。

DESCRIPTION (provided by applicant): Prostate cancer is the most prevalent cancer and is the second major cause of cancer-related deaths among American men. However, little is known about the etiology of prostate cancer and the risk factors for advanced disease. Recently, dietary influences that may alter methylation patterns in DNA have been implicated in the etiology of various cancers. However, few investigators have examined the relationship between DNA methylation and genotypes that may be associated with prostate cancer. The objective of this proposal is to explore the potential relationship between prostate cancer and the major genes affecting DNA methylation through folate metabolism pathways. We hypothesize (1) that both biological and environmental factors influence prostate cancer onset in sporadic cases and (2) that ethnic/cultural differences in these factors may explain racial differences in patterns of disease. The overall aim of this study is to use novel analytical methods to determine whether common variants in select one- carbon metabolizing genes modify the risk of sporadic prostate cancer in a diverse population. The presence of an association may help to identify the course of disease progression and the individuals who are most likely to develop prostate cancer and progress the quickest. The effect of folate on prostate cancer occurrence is likely to involve interactions of genes at various loci and environmental exposures. Therefore, simultaneous consideration of multiple predictors in the context of a carefully designed epidemiologic study is important. The genes to be studied in this research include MTHFR, CBS, MS, MSRR, TS, and SHMT. Novel analytical methods, including CART, haplotype analysis, and trimming and weighting, will be explored. An ongoing currently funded hospital-based case-control study design will be used to accomplish the following three specific aims: (1) To determine the frequencies of genotypes associated with folate metabolism by race/ethnicity; (2) To determine the association between prostate cancer and genotypes associated with one-carbon metabolism; (3) To determine the effect of folate intake and genotype on prostate cancer occurrence and progression.