ATR Mutation in Endometrial Cancer

子宫内膜癌中的 ATR 突变

• 批准号: 8549554
• 负责人: Paul Joseph Goodfellow
• 金额: $ 28.78万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8549554
• 关键词: ATR gene; Adjuvant; Adjuvant Therapy; Ataxia Telangiectasia; Attention; Biological Markers; Biological Response Modifier Therapy; Cancer Patient; Cell Cycle; Cells; Cessation of life; Clinical; Code; Communities; Coupled; DNA; DNA Damage; Data; Decision Making; Defect; Development; Disease; Disease Progression; Early Diagnosis; Endometrial Carcinoma; Enrollment; Event; Excision; Funding; Genetic; Goals; Gynecologic; Gynecologic Oncology Group; Head and Neck Cancer; High Risk Woman; Incidence; Individual; Indolent; Link; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mismatch Repair; Modality; Modeling; Molecular; Molecular Profiling; Mutation; Newly Diagnosed; Normal tissue morphology; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Postoperative Period; Protocols documentation; Radiation; Radiation therapy; Recurrence; Recurrent disease; Resources; Risk; Risk Assessment; Role; Sample Size; Second Primary Neoplasms; Specimen; Staging; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Total Hysterectomy; United States; Woman; chemotherapy; cohort; experience; loss of function; loss of function mutation; lymph nodes; malignant breast neoplasm; mortality; novel; outcome forecast; patient population; predictive modeling; prognostic; response; success; theranostics; tumor

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.

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，大多数患者在早期出现，预后良好。疾病进展和复发与令人沮丧的结局相关。与这种疾病有关的发病率和死亡率正在上升。到目前为止，我们无法确定最终将死于这种疾病的进展和/或复发患者。目前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在其编码序列内具有A10单核苷酸重复序列。该区域是具有缺陷性错配修复的细胞中突变的热点。ATR截短突变与子宫内膜样癌患者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组方案210队列（“子宫内膜癌的分子分期研究”）验证ATR突变作为该患者人群的预后生物标志物。本研究提出了两个具体目标：具体目标1：研究ATR突变在子宫内膜癌患者中的预后意义。我们将检测来自GOG-210研究患者的508例MSI阳性子宫内膜样癌标本中ATR功能缺失突变，并分析ATR突变与临床病理变量（包括无病生存期和总生存期）之间的关系。具体目标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，确定预后效应是否随特定治疗方式而变化将是重要的。这个大的队列，加上辅助治疗的完整和详细的数据，将使我们能够测试突变/治疗的相互作用，探索ATR突变的潜在价值，以预测治疗反应的子宫内膜癌患者（治疗诊断学）。我们将为研究界（通过GOG提供）产生一个长期的DNA资源，用于多项正在进行和即将进行的研究，重点是与子宫内膜癌患者辅助治疗反应相关的分子缺陷。

项目成果

MonoSeq Variant Caller Reveals Novel Mononucleotide Run Indel Mutations in Tumors with Defective DNA Mismatch Repair.

• DOI: 10.1002/humu.23036
• 发表时间: 2016-10
• 期刊: HUMAN MUTATION
• 影响因子: 3.9
• 作者: Walker, Christopher J.;Miranda, Mario A.;O'Hern, Matthew J.;Blachly, James S.;Moyer, Cassandra L.;Ivanovich, Jennifer;Kroll, Karl W.;Eisfeld, Ann-Kathrin;Sapp, Caroline E.;Mutch, David G.;Cohn, David E.;Bundschuh, Ralf;Goodfellow, Paul J.
• 通讯作者: Goodfellow, Paul J.