CLASSIFYING PANCREATIC CANCERS BY METHYLATOR PHENOTYPES

描述(申请人提供)：DNA甲基化对哺乳动物基因组有深远的影响，并与多种肿瘤抑制基因的失活有关。在不同癌症中发现的甲基化基因座的数量存在相当大的差异性。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识别具有不同临床病理特征和新的治疗靶点的癌症亚类。我们已经报道，胰腺癌的一个亚组(称为CIMP+或CpG岛甲基化表型+)在内源性抑癌基因上存在显著更高的DNA甲基化。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。癌症DNA甲基化模式异常的功能基础仍不清楚。我们推测，某些启动子的异常甲基化可能发生在癌变过程中，作为其转录活性变化的结果。我们将通过分析TGFb/Smad4通路激活或抑制转录激活或抑制的基因启动子的甲基化状态来检验这一假设，TGFb/Smad4通路在胰腺癌和其他癌症中通常被突变失活。我们还假设，CIMP+胰腺癌保留了在CIMP-癌中丢失的正常从头甲基化功能。我们推测，一些启动子在癌变过程中由于其转录活性的变化而发生异常甲基化，这些变化是由染色质改变和DNA甲基转移酶的招募所介导的。这项建议的目的已经被国家癌症研究所的项目审查小组(PRG)确定为研究优先事项--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。CIMP胰腺癌分类的临床病理、遗传学和功能相关性将通过以下特定目的来获得：目的1：检验基于甲基化表型的胰腺癌分类的有效性和意义。目的#2：确定特定基因甲基化在胰腺癌中的意义。目的#3：检测胰腺癌的基因改变是否与胰腺癌的异常甲基化有关。目的#4：确定CIMP+与CIMP-胰腺癌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.