CLASSIFYING PANCREATIC CANCERS BY METHYLATOR PHENOTYPES

描述（由申请人提供）：DNA甲基化对哺乳动物基因组具有深远的影响，并涉及多种肿瘤抑制基因的失活。在不同癌症中发现的甲基化基因座的数量存在相当大的变异性。我们假设，基于整体和特定基因甲基化模式的胰腺癌分类将确定具有不同临床病理特征和新治疗靶点的癌症亚组。我们已经报道了胰腺癌的一个子集（称为CIMP+或CpG岛甲基化表型+）在内源性肿瘤抑制基因座处具有显著更高的异常DNA甲基化患病率。我们将根据DNA甲基化模式对胰腺癌进行分类，并确定这些模式的意义。异常癌症DNA甲基化模式的功能基础仍然未知。我们推测，异常甲基化的一些启动子可能会发生在癌变过程中，由于其转录活性的变化。我们将通过分析TGFB/SMAD 4通路（胰腺癌和其他癌症中通常因突变而失活的通路）激活或抑制的转录基因启动子的甲基化状态来验证这一假设。我们还假设CIMP+胰腺癌保留了在CIMP-癌症中丢失的正常从头甲基化功能。我们推测，一些启动子成为异常甲基化在癌变过程中，由于其转录活性的变化，介导的染色质改变和招聘的DNA甲基转移酶。NCI的项目审查小组（PRG）已将该提案的目标确定为研究重点-“确定有助于胰腺癌发展的遗传因素，环境因素和基因-环境相互作用。“胰腺癌CIMP分类的临床病理学、遗传学和功能相关性将通过以下具体目标获得：目标1：测试基于甲基化表型对胰腺癌进行分类的有效性和意义。目的#2：确定胰腺癌中特定基因异常甲基化的意义。目的#3：测试胰腺癌中的遗传改变是否有助于胰腺癌中的异常甲基化。目的#4：确定与CIMP-胰腺癌相比，CIMP+之间是否存在功能性DNA甲基化差异。

DESCRIPTION (provided by applicant): DNA methylation has profound effects on the mammalian genome and is implicated in the inactivation of multiple tumor suppressor genes. Considerable variability exists in the number of methylated loci found in different cancers. We hypothesize that a classification of pancreatic carcinomas based on overall and specific gene methylation patterns will identify subgroups of cancers with a distinct clinicopathological features and with novel therapeutic targets. We have reported that a subset of pancreatic cancers (termed CIMP+ or CpG island methylation phenotype+) harbor a significantly higher prevalence of aberrant DNA methylation at endogenous tumor suppressor loci. We will classify pancreatic cancers based on their DNA methylation patterns and determine the significance of these patterns. The functional basis for the aberrant cancer DNA methylation patterns remain unknown. We hypothesize that aberrant methylation of some promoters may occur during carcinogenesis as a result of changes in their transcriptional activity. We will test this hypothesis by analyzing the methylation status of the promoters of genes transcriptionally activated or repressed by activation of the TGFB/SMAD4 pathway, a pathway commonly inactivated by mutation in pancreatic and other cancers. We also hypothesize that CIMP+ pancreatic cancers retain the normal de novo methylation function that is lost in CIMP- cancers. We hypothesize that some promoters become aberrantly methylated during carcinogenesis as a result of changes in their transcriptional activity, mediated by chromatin alterations and recruitment of DNA methyltransferases. This aims of this proposal have been identified by the program review group (PRG) of the NCI as a research priority-"identify genetic factors, environmental factors, and gene-environment interactions that contribute to development of pancreatic cancer." The clinicopathological, genetic and functional correlates of the CIMP classification of pancreatic cancer will be gained by the following specific aims: Aim #1 : Test the validity and significance of classifying pancreatic cancers based on methylator phenotypes. Aim #2: Determine the significance of aberrant methylation of specific genes in pancreatic cancer. Aim #3: Test whether genetic alterations in pancreatic carcinoma contribute to aberrant methylation in pancreatic cancer. Aim #4: Determine if functional DNA methylation differences exist between CIMP+ compared to CIMP- pancreatic carcinomas.