Human Tumor Analyses

人类肿瘤分析

基本信息

批准号：
8375349
负责人：
William Mallory Grady
金额：
$ 29.88万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8375349
关键词：
Aberrant DNA Methylation Address Adjuvant Adriamycin PFS Affect Aftercare Behavior Biological Biological Assay Biology Breast Cancer Treatment Cancer and Leukemia Group B Cells Clinical Clinical Medicine Clinical Research Clinical Trials Colon Carcinoma Colorectal Cancer Cyclophosphamide DNA Methylation DNA repair protein Data Databases Doxorubicin Enrollment Epigenetic Process Epithelial Family Fluorouracil Frequencies Gene Expression Genes Genetic Genotoxic Stress Human Immunoassay Individual Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Medicine Methylation Molecular Mutate Outcome Patients Proteins Public Health RECQL gene RECQL4 gene RECQL5 gene Rectum Role Sampling Schedule Silicon Dioxide Southwest Oncology Group Staging Technical Expertise Tilia Treatment Protocols Werner Syndrome Work analog base cancer type chemotherapeutic agent chemotherapy cohort common treatment helicase inhibitor/antagonist irinotecan malignant breast neoplasm oncology response tumor

项目摘要

DNA repair proteins affect the response of cells to genotoxic stresses, and are often mutated or silenced in cancers. The RecQ helicases are a family of DNA repair proteins whose inactivation can predispose individuals to cancer (e.g. Werner syndrome, etc.) and can enhance the anti-tumor effects of chemotherapy. The biological significance of inactivation of the RecQ helicases in cancer is largely unknown, although predicted to be of importance based ¿on studies of WRN and BlM in colorectal and breast cancer. Thus, we will assess the expression of the RecQ helicases, BlM, WRN, RECQL, RECQL4, and RECQL5 as well as candidate RECQ helicase interacting proteins in colorectal and breast cancer, and will determine how these proteins affect the responsiveness of these cancers to chemotherapeutic agents, especially TOPO1 inhibitors. Furthermore, WRN and likely the other RecQ helicases can be inactivated in cancer by an epigenetic mechanism-aberrant DNA methylation. Thus, the role of DNA methylation in silencing the RecQ helicases will be assessed and correlated with the clinical behavior of these cancers. The Specific Aims of these studies are: Aim 1: To determine the frequency of loss of expression and epigenetic inactivation of RecQ helicases in common epithelial cancers: colorectal cancer and breast cancer. Aim 2: To determine the role of WRN, BlM, and RECQL4 inactivation and RECQ helicase interacting proteins in modifying the effect of chemotherapy on colorectal cancers (CRC). Aim3: To determine the role of WRN, BlM, and RECQL4 inactivation and RECQ helicase interacting proteins in modulating the effect of chemotherapy on breast cancers (BrCA). In Aims 2 and 3, The RECQ helicase interacting proteins to be studied will be selected from candidates that are genetically or epigenetically altered in CRC or BrCA (e.g. MRE11 and MlH1) and aberrantly expressed. We will determine if methylation or loss of expression of the RECQ helicases and/or intereacting proteins affects sensitivity to chemotherapy by correlating the methylation and expression status of these genes in to response to treatment using two well annotated cohorts from clinical trials (CALBGB 89803 and SWOG S9313). These studies will be done with the support of Core A and Core C as well as Projects 2 and 3.

DNA修复蛋白会影响细胞对遗传毒性应激的反应，并且通常在癌症中突变或沉默。 RECQ解旋酶是一种DNA修复蛋白家族，其失活会使癌症诱发癌症（例如Werner综合征等），并且可以增强化学疗法的抗肿瘤作用。癌症中RECQ解旋酶失活的生物学性在很大程度上是未知的，尽管预计基于结直肠癌和乳腺癌的WRN和BLM的研究至关重要。这是，我们将评估RECQ解旋酶，BLM，WRN，RECQL，RECQL4和RECQL5的表达以及候选RECQ解旋酶相互作用的结直肠癌和乳腺癌中的蛋白质，并将确定这些蛋白如何影响这些癌症对化学治疗剂的反应性，尤其是TOPO1抑制剂。此外，WRN以及其他可能的RECQ解旋酶可以通过表观遗传机理 - 异常的DNA甲基化在癌症中灭活。这是DNA甲基化在沉默的RECQ解旋酶中的作用，将与这些癌症的临床行为进行评估并相关。这些研究的具体目的是：目的1：确定常见上皮癌中RECQ解旋酶的表达丧失和表观遗传灭活的频率：大肠癌和乳腺癌。目标2：确定WRN，BLM和RECQL4灭活和RECQ解旋酶相互作用蛋白在修饰化学疗法对结直肠癌（CRC）的作用方面的作用。 AIM3：确定WRN，BLM和RECQL4失活以及RECQ解旋酶相互作用蛋白在调节化学疗法对乳腺癌（BRCA）的作用中的作用。在AIMS 2和3中，将从遗传或表观遗传学的CRC或BRCA（例如MRE11和MLH1）中选择要研究的RECQ解旋酶相互作用的蛋白并异常表达。我们将通过将这些基因的甲基化和表达状态相关联于使用临床试验的两个良好注释的同类群（CALBGB 89803和SWOG S9313），通过将这些基因的甲基化和表达状态与对治疗的反应相关联，将甲基化或相互作用蛋白的表达丧失影响对化学疗法的敏感性。这些研究将在核心A和Core C以及项目2和3的支持下进行。