ATR Mutation in Endometrial Cancer

描述(申请人提供)：子宫内膜癌是美国最常见的妇科恶性肿瘤，是导致妇科癌症死亡的第二大常见原因。幸运的是，大多数患者出现在早期，预后良好。疾病的进展和复发与惨淡的结局有关。与这种疾病相关的发病率和死亡率正在上升。到目前为止，我们无法确定那些注定要经历进展和/或复发的患者最终将死于这种疾病。迫切需要为子宫内膜癌患者开发有效的预后生物标记物。DNA损伤反应基因ATR在其编码序列中有一个A10单核苷酸重复。这一区域是错配修复缺陷细胞突变的热点。在患有子宫内膜样癌的妇女中，ATR截短突变与复发和死亡率显著增加的风险独立相关。我们建议使用妇科肿瘤组协议210队列(“子宫内膜癌的分子分期研究”)来验证ATR突变作为该患者群体预后生物标记物的有效性。提出了两个特定目标：特定目标1：验证ATR突变在子宫内膜样癌患者预后中的意义。我们将在GOG-210中登记的约508例MSI阳性子宫内膜癌患者样本中检测ATR功能突变，并分析ATR突变与临床病理变量的关系，包括无病和总存活率。具体目标2：确定ATR突变状态与辅助治疗(化疗和/或放射治疗)反应之间的关系。鉴于ATR在DNA损伤反应通路中的重要作用，确定预后效应(S)是否因特定的治疗方法而异将是重要的。这一庞大的队列，加上关于辅助治疗的完整和详细的数据，将使我们能够测试突变/治疗交互作用，探索ATR突变预测子宫内膜样癌(治疗)患者治疗反应的潜在价值。我们将为研究界创建一个长期的DNA资源(通过GOG提供)，用于多项正在进行和即将进行的研究，重点是与子宫内膜样子宫内膜癌患者辅助治疗反应相关的分子缺陷。 公共卫生相关性：该项目将验证ATR突变的预后价值，并测试该生物标记物在子宫内膜样子宫内膜癌患者中的治疗潜力。作为我们对GOG-210样本的表征的一部分，我们将为妇科肿瘤组生成一个持久的肿瘤和匹配的正常组织DNA资源，该资源将用于多个正在进行和即将进行的子宫内膜癌遗传学研究。

DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecologic malignancy in the United States, where it is the second most common cause of gynecologic cancer deaths. Fortunately, most patients present in early stage and have an excellent prognosis. Disease progression and recurrence are associated with dismal outcomes. The incidence and mortality associated with this disease is on the rise. To date, we are unable to identify patients destined to experience progression and/or recurrence who will ultimately die from this disease. There is an urgent need to develop validated prognostic biomarkers for patients with endometrial cancer. The DNA-damage response gene ATR has an A10 mononucleotide repeat within its coding sequence. This region is a hotspot for mutations in cells with defective mismatch repair. ATR truncating mutations are independently associated with a significantly increased risk of recurrence and mortality among women with endometrioid endometrial cancer. We propose to validate ATR mutation as a prognostic biomarker in this patient population using the Gynecologic Oncology Group Protocol 210 cohort ("A molecular staging study of endometrial carcinoma"). Two specific aims are proposed: Specific Aim 1: Validate the prognostic significance of ATR mutation in patients with endometrioid endometrial cancer. We will test for ATR loss of function mutations in an estimated 508 MSI-positive endometrioid endometrial cancer specimens from patients enrolled in GOG-210 and analyze the relationship between ATR mutation and clinicopathologic variables including disease free and overall survival. Specific Aim 2: Determine the relationship between ATR mutation status and response to adjuvant therapy (chemotherapy and/or radiation). Given ATR's important role in DNA damage response pathways, it will be important to determine if prognostic effect(s) vary with specific therapeutic modalities. This large cohort, coupled with complete and detailed data on adjuvant treatment will allow us to test for mutation / therapy interactions, exploring the potential value of ATR mutation to predict response to therapy in patients with endometrioid endometrial cancer (theranostics). We will generate a long-lasting DNA resource for the research community (made available through the GOG) for multiple ongoing and upcoming studies focused on molecular defects related to response to adjuvant therapy in patients with endometrioid endometrial cancer. PUBLIC HEALTH RELEVANCE: This project will validate the prognostic value of ATR mutation and test the theranostic potential of this biomarker in patients with endometrioid endometrial cancer. As part of our characterization of the GOG-210 specimens, we will generate a long-lasting tumor and matched normal tissue DNA resource for the Gynecologic Oncology Group that will be made available for multiple ongoing and upcoming studies on the genetics of endometrial carcinoma.