Prostate cancer and genes of the one-carbon cycle

描述（由申请人提供）：前列腺癌是最常见的癌症，是美国男性癌症相关死亡的第二大原因。然而，对前列腺癌的病因学和晚期疾病的危险因素知之甚少。最近，可能改变DNA甲基化模式的饮食影响与各种癌症的病因有关。然而，很少有研究者研究DNA甲基化和可能与前列腺癌相关的基因型之间的关系。本研究的目的是探索前列腺癌与叶酸代谢途径中影响DNA甲基化的主要基因之间的潜在关系。我们假设：（1）生物学和环境因素都影响前列腺癌在散发病例中的发病;（2）这些因素中的种族/文化差异可能解释疾病模式的种族差异。本研究的总体目的是使用新的分析方法来确定在选择一碳代谢基因中的常见变异是否改变了不同人群中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发展前列腺癌和进展最快的个体。叶酸对前列腺癌发生的影响可能涉及不同基因座和环境暴露的基因相互作用。因此，在精心设计的流行病学研究中同时考虑多个预测因子是很重要的。本研究所要研究的基因包括MTHFR、CBS、MS、MSRR、TS和SHMT。新的分析方法，包括CART，单体型分析，修剪和加权，将被探索。目前正在进行的一项基于医院的病例对照研究设计将用于实现以下三个具体目标：（1）确定与种族/种族叶酸代谢相关的基因型频率;（2）确定前列腺癌与一碳代谢相关基因型之间的关联;（3）确定叶酸摄入量和基因型对前列腺癌发生和进展的影响。

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.