Molecular Genetics of NAT1 and NAT2 in Prostate Cancer

描述(由申请人提供)： 在美国，前列腺癌是最常见的癌症形式，是男性癌症相关死亡的第二大原因。据估计，2003年将诊断出220,900例新的前列腺癌病例，大约28,900名男子将死于这种疾病。非洲裔美国男性的前列腺癌发病率是世界上最高的，死亡率是高加索男性的两倍多。非洲裔美国人前列腺癌患者确诊时的严重程度也明显更高。前列腺癌的种族和家族史的差异表明，遗传因素在前列腺癌的发病中起着重要作用。 人N-乙酰转移酶1和2(NAT)是参与多种致癌物质代谢的重要酶，在前列腺癌的发生发展中起重要作用。我们的初步数据显示，在高加索人和非裔美国人中，NAT2酶活性的升高与前列腺癌风险的增加密切相关。然而，导致NAT2酶活性较高的遗传因素仍未得到充分的研究。 这项研究旨在系统地研究导致前列腺癌高发病率的高NAT活性的遗传原因。将检查启动子区域(参与控制基因表达的DNA片段)以及NAT1和2的编码区和3‘非编码区，并绘制所有突变/多态图谱。具体的突变组合将被分类和表征，并将分析突变组合与高NA2酶活性之间的相关性。以这种方式，将定义与高NA2活性高度相关的特定突变模式(S)。最后，将在111名非裔美国人和353名高加索前列腺癌患者以及相同数量的种族和年龄匹配的对照组中测量特定的突变模式(S)。将进行统计分析，以评估哪些突变模式与前列腺癌易感性有关。我们预计，在这项研究完成后，潜在的生物标记物(S)(NAT1和2突变的特定模式)将被识别为前列腺癌风险增加的潜在生物标志物。

DESCRIPTION (provided by applicant): In the United States, prostate cancer is the most common form of cancer and is the second leading cause of cancer-related death among men. It is estimated that 220,900 new cases of prostate cancer will be diagnosed and that approximately 28,900 men will die of the disease in 2003. African-American men have the world's highest incidence of prostate cancer and more than twice the death rate compared with Caucasian men. African-American prostate cancer patients also have significantly higher rate of severity at diagnosis. The differences in race and family history of prostate cancer suggest that genetic factors play an important role in causing prostate cancer. Human N-acetyl-transferase 1 and 2 (NAT) are very important enzymes involved in the metabolism of a variety of carcinogenic compounds and are postulated to play a critical role in the development of prostate cancer. Our preliminary data has shown that elevated NAT2 enzyme activity is strongly associated with increased risk of prostate cancer in both Caucasian and African-American men. However, the genetic factors contributing to high NAT2 enzyme activity remain under-explored. This research is proposed to systematically investigate the genetic reasons responsible for high NAT activity that contribute to high incidence of prostate cancer. The promoter regions (a fragment of DNA involved in controlling gene expression) along with the coding and 3'UTR regions of NAT1 and 2 will be examined and all mutations/polymorphisms will be mapped. The specific combinations of mutations will be categorized and characterized and the correlation between mutation combinations and high NAT2 enzyme activity will be analyzed. In this manner, specific pattern(s) of mutations that are highly associated with high NAT2 activity will be defined. Finally, the specific pattern(s) of mutations will be measured in 111 African-American and 353 Caucasian prostate cancer patients, as well as in the same number of race and age matched controls. Statistical analysis will be conducted to assess which patterns of mutations are associated with prostate cancer susceptibility. We envision, upon completion of this study, that potential biomarker(s) (specific patterns of NAT1 and 2 mutations) for increased odds of prostate cancer would be identified.