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Methylomic basis of survival disparities among Black and White women with high-grade serous ovarian cancer

患有高级别浆液性卵巢癌的黑人和白人女性生存差异的甲基组学基础

基本信息

批准号：
10561082
负责人：
Lauren Cole Peres
金额：
$ 70.6万
依托单位：
H. LEE MOFFITT CANCER CTR & RES INST
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-01 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10561082
关键词：
Accounting African American Age B-Lymphocytes Behavior Black race CD8B1 gene Cancer Patient Cancer Prognosis Cells Cessation of life Characteristics Cox Models Cytosine Cytotoxic T-Lymphocytes DNA Methylation Data Development Diagnosis Diagnostic Diet Dimensions Disparate Disparity Economics Education Endothelial Cells Epidemiology Epithelial Cells Epithelial ovarian cancer Ethnic Population Gene Expression Genetic Guanine Nucleotides Guidelines Health Services Accessibility Immune Life Style Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Measures Methods Methylation Minority Minority Groups Modeling Molecular Molecular Target Natural Killer Cells North Carolina Nurses&apos Health Study Obesity Observational Study Outcome Ovarian Serous Adenocarcinoma Phenotype Physical activity Population Population Study Prevention strategy Prognosis Prognostic Factor Race Regulator Genes Regulatory T-Lymphocyte Reporting Research Resources Serous Site Smoking Smoking Status Stromal Cells Testing Time Tissues Underrepresented Minority Weight Woman Work bead chip black women cancer epidemiology cancer survival cell type clinical decision-making differences in access disease heterogeneity disparity reduction eosinophil epidemiology study genome-wide improved individualized prevention innovation methyl group methylation biomarker methylation pattern methylomics monocyte mortality mortality risk neutrophil novel ovarian neoplasm personalized medicine preventive intervention racial determinant racial difference racial minority population racial population social social culture study population survival disparity targeted treatment tumor tumor DNA tumor microenvironment

项目摘要

ABSTRACT Epithelial ovarian cancer is the deadliest gynecologic malignancy among women, with less than half of women surviving five years after diagnosis. Black women with ovarian cancer have worse survival compared to White women. The causes of these disparities remain elusive as prior research suggests that it is not entirely due to differential access to care or guideline-adherent treatment. Thus, it remains a high priority to uncover approaches to reduce mortality and improve survival, especially for Black women. However, the majority of research on ovarian cancer is from White women, which has hindered the discovery of novel factors important for prognosis in underrepresented minority groups. Here, we will leverage epidemiologic, molecular, and outcome data from well-established observational studies to investigate the methylomic basis of ovarian cancer survival disparities between Black and White women. DNA methylation provides a unique opportunity to investigate disparities as lifestyle and sociocultural conditions that are disparate between racial/ethnic groups may manifest as alterations in tumor DNA methylation, resulting in phenotypic differences between populations. We hypothesize that Black women will have a different composition of methylation patterns or a unique tumor DNA methylation signature associated with poorer survival compared to White women. To limit contributions of disease heterogeneity, we will focus on the most common and one of the deadliest histotypes, high-grade serous ovarian carcinoma (HGSOC). Among 239 Black and 478 White women with HGSOC, tumor DNA methylation will be measured using the Illumina MethylationEPIC array. Frist, data dimension reduction methods will be used to determine tumor DNA methylation signatures that are associated with survival among the overall study population and among Black and White women separately, identifying differentially methylated regions associated with outcomes that are specific to each race and those that are shared across race. These signatures will be validated among an additional 200 Black and 200 White women with HGSOC. Second, the association between pre- diagnostic exposures that have the potential to alter DNA methylation states (e.g., age at diagnosis, smoking status) and outcome-associated DNA methylation signatures will be investigated to determine which factors may be informative for preventive strategies. As DNA methylation is highly tissue specific, the DNA methylation signature of the tumor is a weighted mixture of the methylation signature for each of the cells within the tumor. Therefore, in the third aim, we will infer cell composition from tumor DNA methylation data using a novel cell mixture deconvolution method, and examine whether inferred cell composition is associated with risk of mortality. Comparing DNA methylation across populations has important applications as this work will advance the discovery of molecular targets among an underrepresented racial minority group, aiding in clinical decision- making and informing the development of personalized therapies to reduce mortality in Black women and ultimately reduce the survival gap between Black and White women with ovarian cancer.

摘要