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（由适用提供）：本文概述的计划的总体目标是使Sarah Nechuta博士在乳腺癌生存的分子流行病学领域启动她独立的职业。 Nechuta博士是范德比尔特大学医学中心的终身训练助理教授。 Nechuta博士对癌症流行病学学术生涯以及成为独立科学家的潜力的承诺得到了她的出版物，合作和获得资金的最初成功的证明。但是，要成功地领导多学科团队在乳腺癌生存的分子流行病学中进行新颖和有影响力的研究，需要进行额外的训练。她在乳腺癌流行病学和生活方式因素方面具有强大的背景，但在分子流行病学方面的经验有限，特别是在遗传流行病学方面。她还缺乏在癌症生存中进行研究研究的经验和进行研究的经验。在与导师的密切合作中，她开发了一个新颖而重要的研究项目，并结合了一项严格的教学和动手训练计划，在遗传学，生物信息学，癌症生物学和肿瘤学方面。她的导师包括一个跨学科的团队组成的成熟科学家，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。 TNBC具有侵略性，预后不良，标准治疗方法是化学疗法和放疗。 DNA修复机制在癌症治疗效率和毒性以及预后中至关重要。但是，与乳腺癌结局有关的DNA修复能力尚未得到充分研究，所有先前的研究都仅限于一个或一个精选的少数选择变体，而无研究已经考虑了种系和肿瘤遗传变异。利用两项基于人群的乳腺癌存活研究（总TNBC（n = 747））具有可用的生物样品（包括量化的肿瘤组织mRNA表达水平），我们提出了一种新型且与生物学相关的方法来评估TNBC预后中DNA修复。具体目的包括：1）使用使用功能种系遗传变异构建的遗传评分来评估DNA修复能力，并确定了每个DNA修复途径的先验性，并合并了多个途径（适当）； 2）评估来自乳腺肿瘤组织的多个DNA修复基因表达生物标志物与TNBC结局相关； 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预后中的关节作用； 4）进行一项试点研究，以制定和测试建立非裔美国人乳腺癌存活群体的方案。该CDA将为Nechuta博士提供研究分子和遗传标志物的专业知识，以及生物标志物与生活方式因素之间的相互作用，在大多学生种群中的乳腺癌存活中。她将基于该计划进行自己的研究，包括对非裔美国乳腺癌存活的大规模研究，使她能够在乳腺癌生存的分子流行病学中建立独立性。