rDNA Methylation and prognosis in Endometrial Cancers

描述（由申请人提供） 子宫内膜癌是美国最常见的原发性妇科恶性肿瘤，每年诊断出超过39，000例新病例。在美国，大多数女性都患有子宫内膜样癌。这种组织学亚型预后良好，5年总生存率接近90%。尽管大多数患者可以通过手术治愈，但复发性卵巢样腺癌是死亡的重要原因。辅助放射治疗，试图消除任何剩余的肿瘤细胞，往往是治疗计划的一部分，为妇女谁是在复发性疾病的风险增加。在早期（I和II期）子宫内膜癌患者中，辅助治疗的使用和益处存在争议。放射治疗有很大的并发症风险。 此外，放射治疗的成本相当可观。在一项关于中危类卵巢腺癌辅助治疗的大型多中心随机试验中，证实盆腔放疗可显著降低复发率，但仅对总生存率产生较小的、无统计学意义的改善。 有必要在辅助放射治疗带来的增加的费用和发病率与减少中度风险疾病妇女的复发率之间找到平衡。一种分子标记物来识别那些复发风险非常低的患者可以帮助避免不必要的辅助治疗，并通过这样做，减少与治疗子宫内膜癌相关的发病率和费用。 相反，高风险疾病的标志物可以帮助靶向辅助治疗的使用。此外，在子宫切除术前识别出那些患侵袭性或致命性疾病风险较高的妇女的能力，可能会对如何照顾这组妇女产生积极影响。在此提出的标记物研究的长期目标是在前瞻性随机试验中将联合收割机分子分层和常规风险评估结合起来。 在本申请中，我们提出了一种新的方法来分析甲基化的rDNA序列在临床肿瘤标本。我们以前证明rDNA甲基化是子宫内膜样腺癌患者的独立预后标志。我们将开发1）焦磷酸测序TM方法来评估肿瘤DNA中rDNA甲基化，2）将rDNA焦磷酸测序TM甲基化分析应用于临床标本（石蜡包埋、福尔马林固定的子宫切除术和子宫切除术前的活组织检查）和3）在R33期的应用，我们将使用这些方法来评估焦磷酸测序TM rDNA甲基化在一系列连续的妇女中的预后和诊断意义，类腺癌。这些研究旨在确定肿瘤rDNA甲基化是否可以作为子宫内膜癌患者子宫切除术前和子宫切除术后标本的预后和诊断标志物，rDNA甲基化分析最终可以用于帮助指导子宫内膜癌患者的治疗

DESCRIPTION (provided by applicant) Endometrial cancer is the most common primary gynecologic malignancy in the United States, with over 39,000 new cases diagnosed each year. Most women in the US present with endometrioid endometrial carcinoma. This histologic subtype carries a favorable prognosis, with an overall 5-year survival that approaches 90%. Despite the fact that most patients are cured with surgery, recurrent endometrioid adenocarcinoma is a significant cause of mortality. Adjuvant radiation therapy, given in an attempt to eliminate any remaining tumor cells, is often a part of the treatment plan for women who are at increased risk for recurrent disease. In women with early stage (I and II) endometrial carcinoma, the use and benefits of adjuvant therapy are controversial. Radiation therapy carries a significant risk for complications. Furthermore, the costs for radiation therapy are considerable. In a large multicenter randomized trial of adjuvant therapy for intermediate risk endometrioid adenocarcinoma, it was demonstrated that pelvic radiation significantly decreased recurrences but brought about only a small, non-statistically significant improvement in overall survival. There is a need to find a balance between the increased cost and morbidity that comes with adjuvant radiation therapy, and the reduction in the recurrences for women with intermediate risk disease. A molecular marker to identify those patients who are at very low-risk for recurrence could help avoid unnecessary adjuvant therapy and by doing so, lessen the morbidity and expense associated with treating endometrial cancer. Conversely, a marker for high-risk disease could help target the use of adjuvant therapy. Furthermore, the ability to recognize those women at higher risk for aggressive or deadly disease prior to hysterectomy could have a positive effect on how this group of women is cared for. The long-term goal for the marker studies proposed here is to combine molecular stratification and conventional risk assessment in prospective randomized trials. In this application we propose to develop a new method to analyze methylation of rDNA sequences in clinical tumor specimens. We previously demonstrated that rDNA methylation was an independent prognostic marker in patients with endometrioid endometrial adenocarcinoma. We will develop 1) Pyrosequencing TM methods to assess rDNA methylation in tumor DNAs, 2) apply the rDNA Pyrosequencing TM methylation analyses to clinical specimens (paraffin-embedded, formalin-fixed hysterectomy and pre-hysterectomy, biopsies) and 3) in the R33 phase of the application, we will use these methods to assess the prognostic and diagnostic significance of Pyrosequencing TM rDNA methylation in a consecutive series of women with endometrioid adenocarcinoma. These studies are designed to determine whether tumor rDNA methylation could serve as a prognostic and diagnostic marker in both pre-hysterectomy and hysterectomy specimens from women with endometrial cancer, rDNA methylation analyses could ultimately be used to help guide the treatment of endometrial cancer patients