Methylation Markers for Prognosis in Endometriod Endometrial Cancers

项目2的目的是鉴定用于预测早期（阶段）复发的表观遗传生物标志物 1和II）类神经胶质瘤样子宫内膜癌（EEC）。虽然这种类型的癌症通常具有良好的 预后，约10%的患者在诊断后3年内出现局部复发或远处转移。 然而，目前使用的临床病理学参数不足以预测哪些患者 在他的分子标记档案中，“复发和缺失是第一次” 最近已被证明是重要的改善预后和更好的分层癌症 亚型我们的初步研究发现，CpG岛高甲基化，一种表观遗传学上的 在癌症中的改变，代表了未开发的用于EEC的生物标志物资源。识别这些 甲基化调控位点，我们将遵循NCI早期检测建立的基于阶段的方法， 中国互联网.在发现步骤（I期）中，将使用表观遗传微阵列方法来 全面筛选54例早期原发性肿瘤中27，000个人类CpG岛的甲基化改变 分期复发患者和54例非复发患者（样本量合理）。全球概况分析将 鉴定在复发组中频繁高甲基化而在非复发组中不高甲基化的候选基因座。 组在验证阶段（第II阶段），将使用基于PCR的测定法COBRA来确认甲基化 在第二个队列中的54名早期复发患者和54名非复发患者的研究结果。最后一组 30个基因座将用于进一步分析2315个EEC（包括所有临床分期和肿瘤分级） III期回顾性研究。一种名为MassARRAY的稳健检测方法可以有效地定量甲基化 单次运行中384个临床样本中的CpG位点。这项广泛的研究将确定是否确定 基因座也是一些EEC患者的不良预后指标。临床敏感性和特异性 有希望的生物标志物将被计算并用于评估患者的复发，无病生存， 其他临床病理参数。这样的研究为未来的前瞻性临床试验奠定了基础 （IV期）旨在测试表观遗传生物标志物用于准确预测复发性EEC的效用。 相关性（参见说明）： 这项工作的提出将导致双方的子宫内膜癌生物学和新的理解 检测、预防和治疗子宫癌的方法， 发病率和死亡率。

The objective of Project 2 is to identify epigenetic biomarkers for predicting recurrence of early stage (stages 1 and II) endometrioid endometrial carcinomas (EECs). While this type of cancer usually has a good prognosis, ~10% of patients present with local recurrence or distant metastasis within 3 years of diagnosis. The currently used clinicopathojogical parameters, however, are inadequate for predicting which patients are IiReTy to'recur andlwoijldlnosf beTiefirfrohTup^ Inlhis regardTpfofiIing of molecular markers"~ has recently been shown to be important for improved prognosis and for better stratification of cancer subtypes. Our preliminary studies have found that CpG island hypermethylation, a type of epigenetic alteration in cancer, represents an untapped resource of biomarkers for EECs. To identify these methylation-regulated loci, we will follow a phased-based approach established by the NCI's Early Detection Research Network. In the discovery step (Phase I), an epigenetic microarray approach will be used to comprehensively screen altered methylation of 27,000 human CpG islands in primary tumors of 54 early stage patients who recurred and 54 non-recurrent patients (sample size justified). Global profiling will identify candidate loci that are frequently hypermethylated in the recurrent group, but not in the non-recurrent group. In the validation phase (Phase II), a PCR-based assay, COBRA, will be used to confirm methylation findings in a second cohort of 54 early stage patients who recurred and 54 non-recurrent patients. A final set of 30 loci will then be used for further analysis in 2315 EECs (including all clinical stages and tumor grades) in the Phase III retrospective study. A robust assay, called MassARRAY, can efficiently quantify methylated CpG sites in 384 clinical samples in a single run. This extensive study will determine whether the identified loci are also poor prognostic indicators for some EEC patients. Clinical sensitivity and specificity of promising biomarkers will be calculated and used to assess patients' recurrence, disease-free survival, and other clinicopathological parameters. Such a study lays the foundation for a future prospective clinical trial (Phase IV) designed to test the utility of epigenetic biomarkers for accurate prediction of recurrent EECs. RELEVANCE (See instructions): The work proposed will lead to both an improved understanding of endometrial cancer biology and new approaches to the detection, prevention and treatment of uterine cancers which will result in reduced cancer morbidity and mortality.