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有深远的影响，并涉及多种肿瘤抑制基因的失活。在不同的癌症中发现的甲基化位点的数量存在相当大的差异。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群。我们已经报道了胰腺癌的一个亚群（称为CIMP+或CpG岛甲基化表型+）在内源性肿瘤抑制位点具有明显更高的异常DNA甲基化发生率。我们将根据其DNA甲基化模式对胰腺癌进行分类，并确定这些模式的重要性。异常癌症DNA甲基化模式的功能基础仍然未知。我们假设一些启动子的异常甲基化可能在癌变过程中发生，这是它们转录活性变化的结果。我们将通过分析TGFB/SMAD4通路激活或抑制的基因启动子的甲基化状态来验证这一假设，TGFB/SMAD4通路在胰腺癌和其他癌症中通常因突变而失活。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。我们假设一些启动子在癌变过程中由于其转录活性的改变而异常甲基化，这是由染色质改变和DNA甲基转移酶的募集介导的。该提案的目的已被NCI的项目评审小组（PRG）确定为研究重点——“确定导致胰腺癌发展的遗传因素、环境因素和基因-环境相互作用”。将通过以下具体目标获得CIMP胰腺癌分类的临床病理，遗传和功能相关性：目的#1：测试基于甲基化表型分类胰腺癌的有效性和意义。目的2：确定胰腺癌中特定基因异常甲基化的意义。目的3：检测胰腺癌的基因改变是否会导致胰腺癌的异常甲基化。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.