DNA Repair Pathways in Triple Negative Breast Cancer Outcomes

三阴性乳腺癌结果中的 DNA 修复途径

基本信息

批准号：
8891733
负责人：
Sarah Jean Nechuta
金额：
$ 12.97万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8891733
关键词：
Academic Medical Centers Affect African American Bioinformatics Biological Biological Markers Breast Breast Cancer Epidemiology Breast Cancer Patient Breast Cancer survivor Breast Cancer survivorship Cancer Biology Cancer Survivor Cancer Survivorship Caring Chemotherapy-Oncologic Procedure Cohort Studies Collaborations Cyclophosphamide DNA DNA Damage DNA Repair DNA Repair Gene DNA Repair Pathway Data Development ERBB2 gene ERCC1 gene ERCC2 gene EXO1 gene Evaluation Female Funding Future Gene Expression Genes Genetic Genetic Markers Genetic Polymorphism Genetic Variation Genomic Instability Health Individual Differences Interview Investigation Joints Knowledge Lead Malignant Neoplasms Mammary Neoplasms Measures Medicine Mentors Mentorship Molecular Molecular Epidemiology Morbidity - disease rate Neoplasm Metastasis Outcome Oxidative Stress Participant Pathway interactions Patients Pilot Projects Population Heterogeneity Prospective Studies Protocols documentation Publications Quality of life Radiation therapy Recurrence Research Research Project Grants Risk Role Sampling Scientist TOP2A gene Testing Therapeutic Intervention Topoisomerase II Toxic effect Training Training Programs Treatment Effectiveness Treatment Efficacy Tumor Subtype Tumor Tissue Variant XRCC1 gene base cancer care cancer cell cancer epidemiology cancer recurrence cancer therapy career chemotherapy cohort compliance behavior crosslink design experience follow-up genetic epidemiology genetic variant improved intercalation killings lifestyle factors mRNA Expression malignant breast neoplasm molecular marker mortality multidisciplinary neoplastic cell non-compliance novel oncology outcome forecast personalized cancer therapy population based professor programs research study standard care success targeted treatment triple-negative invasive breast carcinoma tumor tumor DNA tumor progression

项目摘要

DESCRIPTION (provided by applicant): The overall objective of the program outlined herein is to enable Dr. Sarah Nechuta to launch her independent career in molecular epidemiology of breast cancer survivorship. Dr. Nechuta is a tenure-track assistant professor of medicine at the Vanderbilt University Medical Center. Dr. Nechuta's commitment to an academic career in cancer epidemiology, and potential to be an independent scientist is demonstrated by her publications, collaborations, and initial success in obtaining funding. However, to successfully lead multidisciplinary teams to conduct novel and impactful investigations in the molecular epidemiology of breast cancer survivorship, additional training is needed. She has a strong background in breast cancer epidemiology and lifestyle factors, but limited experience in molecular epidemiology, particularly in genetic epidemiology. She also lacks experience in the hands-on design and conduct of research studies among cancer survivors. In close collaboration with her mentors, she has developed a novel and significant research project, combined with a rigorous didactic and hands-on training program in genetics, bioinformatics, cancer biology, and oncology. Her mentors include a multidisciplinary team of established scientists with expertise in molecular and genetic epidemiology, statistical genetics, bioinformatics, cancer survivorship, and oncology. TNBCs are aggressive with a poor prognosis, and standard treatment is chemotherapy and radiotherapy. DNA repair mechanisms are critically important in cancer treatment efficacy and toxicity, and prognosis. However, the role of DNA repair capability in relation to breast cancer outcomes has not been adequately investigated, with all previous studies limited to only one or a select few select variants, and no studies have considered both germline and tumor genetic variation. Utilizing two population-based studies of breast cancer survivors (total TNBCs (n=747)) with available biological samples (including quantified tumor tissue mRNA expression levels) we propose a novel and biologically relevant approach to evaluate DNA repair in TNBC prognosis. Specific aims include: 1) to evaluate DNA repair capability using genetic scores constructed using functional germline genetic variants identified a priori for each DNA repair pathway, and multiple pathways combined (as appropriate); 2) to evaluate multiple DNA repair gene expression biomarkers from breast tumor tissue in association with TNBC outcomes; 3) to evaluate the joint effect of germline DNA repair capability and tumor DNA repair gene expression biomarkers in the prognosis of TNBC; and 4) to conduct a pilot study to develop and test protocols for establishing a cohort of African American breast cancer survivors. This CDA will provide Dr. Nechuta with the expertise to study molecular and genetic markers, and interactions between biomarkers and lifestyle factors, in breast cancer survivorship in diverse populations. She will build on this program to conduct her own studies, including a large-scale study among African American breast cancer survivors, enabling her to establish her independence in the molecular epidemiology of breast cancer survivorship.

描述（由申请人提供）：本文概述的计划的总体目标是使 Sarah Nechuta 博士能够在乳腺癌生存的分子流行病学领域开展她的独立职业生涯。 Nechuta 博士是范德比尔特大学的终身教授医学助理教授。 Nechuta 博士致力于癌症流行病学的学术事业，并通过她的出版物、合作和成功领导的初步成功证明了她成为一名独立科学家的潜力。她在乳腺癌流行病学和生活方式因素方面拥有深厚的背景，但在分子流行病学，特别是遗传流行病学方面的经验有限。她在癌症幸存者的实践设计和开展研究方面拥有丰富的经验，她与导师密切合作，开发了一个新颖且重要的研究项目，并结合了严格的遗传学教学和实践培训计划，她的导师包括一个由在分子和遗传流行病学、统计遗传学、生物信息学、癌症生存和肿瘤学方面具有专业知识的多学科科学家组成的TNBC，其预后不良，标准治疗是化疗和化疗。然而，DNA 修复机制在癌症治疗的疗效、毒性和预后中发挥着至关重要的作用。与乳腺癌结果相关的 DNA 修复能力尚未得到充分研究，之前的所有研究仅限于一种或少数选定的变异，并且没有研究考虑了种系和肿瘤遗传变异，利用两项基于乳腺癌幸存者（总 TNBC（n = 747））的研究以及可用的生物样本（包括量化的肿瘤组织 mRNA 表达水平），我们提出了一种新颖且生物学相关的方法。评估 TNBC 预后中的 DNA 修复，具体目标包括：1) 使用先验确定的每个 DNA 修复途径和多种途径组合的功能性种系遗传变异构建的遗传评分来评估 DNA 修复能力（如适用）；评估乳腺肿瘤组织中的多种 DNA 修复基因表达生物标志物与 TNBC 结局的关系；3) 评估种系 DNA 修复能力和肿瘤 DNA 修复基因表达生物标志物在 TNBC 预后中的联合作用；4) 开展试点研究；该 CDA 将为 Nechuta 博士提供研究分子和遗传标记以及生物标记与生活方式因素之间在不同人群乳腺癌生存中的相互作用的专业知识。将在此基础上建立计划进行自己的研究，包括对非裔美国乳腺癌幸存者进行的大规模研究，使她能够在乳腺癌幸存者的分子流行病学方面建立独立性。