DNA Repair Pathways in Triple Negative Breast Cancer Outcomes

Vanderbilt University, Nashville TN

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Abstract

? 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.