ATR Mutation in Endometrial Cancer

描述（由申请人提供）：子宫内膜癌是美国最常见的妇科恶性肿瘤，是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。疾病进展和复发与令人沮丧的结果相关。与这种疾病有关的发病率和死亡率正在上升。到目前为止，我们无法确定注定会经历进展和/或复发并最终死于这种疾病的患者。迫切需要为子宫内膜癌患者开发有效的预后生物标志物。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。该区域是错配修复缺陷细胞突变的热点。ATR截断突变与子宫内膜样子宫内膜癌女性复发和死亡风险显著增加独立相关。我们建议使用妇科肿瘤学组协议210队列（“子宫内膜癌的分子分期研究”）验证ATR突变作为该患者群体的预后生物标志物。提出两个具体目的：具体目的1：验证ATR突变在子宫内膜样子宫内膜癌患者中的预后意义。我们将测试来自GOG-210项目患者的约508例msi阳性子宫内膜样子宫内膜癌标本中的ATR功能缺失突变，并分析ATR突变与临床病理变量（包括无病生存和总生存）之间的关系。特异性目的2：确定ATR突变状态与辅助治疗（化疗和/或放疗）反应之间的关系。鉴于ATR在DNA损伤反应途径中的重要作用，确定预后效果是否随特定治疗方式而变化将是很重要的。这个庞大的队列，加上完整和详细的辅助治疗数据，将使我们能够测试突变/治疗相互作用，探索ATR突变在预测子宫内膜样子宫内膜癌患者治疗反应方面的潜在价值（治疗学）。我们将为研究界提供一个长期的DNA资源（通过GOG提供），用于多项正在进行和即将进行的研究，重点关注与子宫内膜样子宫内膜癌患者对辅助治疗反应相关的分子缺陷。

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.