Aberrant DNA methylation patterns of miRNAs and breast cancer racial disparities

miRNA 的异常 DNA 甲基化模式与乳腺癌种族差异

• 批准号: 8700870
• 负责人: Zhihong Gong
• 金额: $ 14.4万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700870
• 关键词: Aberrant DNA Methylation; Address; Affect; African; African American; Age; Aggressive Clinical Course; American; Archives; Area; Award; Bioinformatics; Biological; Biological Factors; Biological Markers; Biometry; Cancer Biology; Case-Control Studies; Code; Collaborations; Complex; DNA; DNA Methylation; DNA Sequence; Data; Development; Diagnosis; Diet; Dietary Factors; Disease; Educational workshop; Environmental Risk Factor; Epidemiologist; Epigenetic Process; Estrogen Receptor Status; Estrogen receptor negative; European; Family; Foundations; Freezing; Functional RNA; Funding; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Health; High Risk Woman; High-Throughput Nucleotide Sequencing; Human; Incidence; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Life Style; Link; Literature; Malignant Neoplasms; Mammary Neoplasms; Medicine; Mentors; Mentorship; Messenger RNA; Methods; Methylation; MicroRNAs; Molecular; Molecular Carcinogenesis; Molecular Epidemiology; Molecular Epidemiology of Cancer; Pathology; Patients; Pattern; Phenotype; Play; Population; Predisposition; Prevention strategy; Preventive; Proteins; Public Health; Questionnaires; Race; Recurrence; Research; Research Personnel; Research Project Grants; Research Training; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Role; Roswell Park Cancer Institute; Sampling; Solid; Statistical Methods; Techniques; Therapeutic; Tissue Sample; Tissues; Training; Tumor Tissue; Woman; Work; Writing; anticancer research; base; cancer epidemiology; cancer health disparity; cancer prevention; cancer risk; carcinogenesis; career; experience; genome wide methylation; genome-wide; health disparity; high risk; improved; interest; lifestyle factors; malignant breast neoplasm; novel; nutrition; outcome forecast; population based; programs; pyrosequencing; racial difference; skills; symposium; therapeutic target; tumor

DESCRIPTION (provided by applicant): Background: Breast cancer incidence is higher in women of European ancestry (EA) than in women of African ancestry (AA) overall, yet AA women are more likely to be diagnosed with estrogen receptor negative, high histological grade tumors that are associated with an overall more aggressive clinical course and poor prognosis. The reasons for these disparities in breast cancer remain unknown; however, environmental and lifestyle risk factors clearly contribute to an increased susceptibility for biologically aggressive types of the disease in AA women. Importantly, recent progress in breast cancer research has indicated that the biological mechanisms behind the association may lie in the ability of these risk factors to modulate DNA methylation, thus potentially altering the gene expression and contributing to cancer racial differences. Further, aberrant DNA methylation of microRNAs (miRNAs) may have a much broader effect than altering the methylation level in protein-coding genes, because a single miRNA can regulate expression of multiple target genes. However, to our knowledge, no study has examined the impact of aberrant DNA methylation of miRNAs on breast cancer disparities and whether and how environmental and lifestyle risk factors play a role in this relationship. Research and Training Plan: We propose to study aberrant DNA methylation in miRNAs, an understudied area, and its association with dietary and lifestyle factors, in relation to breast cancer racial disparities. This proposed study utilizes the data generated from a genome-wide methylation analysis in breast tumor tissue from AA and EA women using the Illumina Infinity 450K array platform and from a large case-control study, the Women's Circle of Health Study (WCHS), with biospecimens and extensive questionnaire data from AA and EA women with breast cancer. In Aim 1, we first propose to select miRNA that are differentially methylated by race and ER status from the genome-wide array, and verify these by an independent, high-throughput sequencing-based methylation analysis method; we will also assess miRNA expression levels. In Aim 2, we will further examine the differentially methylated loci in depth in tumors from 500 AA and 500 EA patients participating in WCHS. Lastly in Aim 3, we will examine associations between miRNA methylation patterns and various dietary and lifestyle factors, and their role in relation to breas cancer racial differences between AA and EA women. While my previous experience and training in medicine, nutrition, and cancer epidemiology provides a solid foundation for me to pursue the proposed research interests, I have limited knowledge and expertise in molecular epidemiology, particularly in epigenetics, and analysis of complex data, and their applications to human populations. This career development award will provide me the opportunity to gain training and mentoring in several targeted areas, including knowledge in breast cancer biology, molecular carcinogenesis and the role of miRNAs, advanced methods and techniques in genetic/epigenetics, skills in biostatistics and bioinformatics, and general training in the ethica conduct of scientific research, grant writing and development. New knowledge and skills in these areas will be obtained through mentorship (Drs. Christine Ambrosone, Michael Higgins, Song Liu, and Steven Belinsky),formal courses, practical laboratory training, seminars, workshops, and conferences. The experience and knowledge gained from this award will ultimately prepare me to develop and submit a R01 application for funding that is necessary to establish myself as an independent researcher. Objective: The main objective of this career development award is to gain training and mentoring in above mentioned targeted areas in order to develop and expand my career as a cancer epidemiologist with a deeper and comprehensive knowledge of DNA methylation and miRNAs and their roles in carcinogenesis and cancer prevention. My long-term goal is to develop expertise and be able to integrate the most current epigenetic, molecular and statistical methods into population-based studies, especially to study the contribution of epigenetic alterations and their associations with environmental, dietary and lifestyle factors in relation to cancer risk. I am particularly interestd in breast cancer and racial disparities, but also would like to apply the knowledge and skills gained through this training to other cancers. In summary, this career development award will provide me invaluable experience for a successful transition into scientific independence in molecular cancer epidemiology with a focus on epigenetics and its role of cancer prevention. Cancer Relevance: The proposed work addresses an understudied area of breast cancer and will contribute to the limited literature for a better understanding of the epigenetic role, in particular aberrant methylation on miRNAs, in breast cancer racial disparities. We will also be able to evaluate modifiable factors that are associated with aberrant methylation patterns. Findings could provide important information for the discovery of novel biomarkers and the development of targeted preventive and therapeutic strategies.

背景：总体而言，欧洲血统女性（EA）的乳腺癌发病率高于非洲血统女性（AA），但AA女性更有可能被诊断为雌激素受体阴性、高组织学分级的肿瘤，这些肿瘤总体上更具侵袭性的临床病程和不良预后。乳腺癌中存在这些差异的原因尚不清楚；然而，环境和生活方式风险因素明显增加了AA妇女对生物侵袭型疾病的易感性。重要的是，乳腺癌研究的最新进展表明，这种关联背后的生物学机制可能在于这些风险因素调节DNA甲基化的能力，从而可能改变基因表达并导致癌症的种族差异。此外，microrna （miRNA）的异常DNA甲基化可能比改变蛋白质编码基因的甲基化水平具有更广泛的影响，因为单个miRNA可以调节多个靶基因的表达。然而，据我们所知，还没有研究调查过mirna异常DNA甲基化对乳腺癌差异的影响，以及环境和生活方式风险因素是否以及如何在这种关系中发挥作用。研究和培训计划：我们建议研究mirna中的异常DNA甲基化，这是一个研究不足的领域，以及它与饮食和生活方式因素之间的关系，以及与乳腺癌种族差异的关系。这项提议的研究