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

• 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
• 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' 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

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.

抽象的 上皮卵巢癌是女性最致命的妇科恶性肿瘤，不到一半的妇女 诊断后五年存活。与白人相比，卵巢癌的黑人妇女的生存率较差 女性。这些差异的原因仍然难以捉摸，因为先前的研究表明，这并不完全是由于 获得护理或准则遵守治疗的差异。因此，发现方法仍然是一个很高的优先事项 降低死亡率并提高生存率，尤其是对于黑人妇女。但是，大多数研究 卵巢癌来自白人妇女，这阻碍了发现对预后很重要的新因素 在代表性不足的少数群体中。在这里，我们将利用来自的流行病学，分子和结果数据 良好的观察性研究以研究卵巢癌存活差异的甲基组基础 在黑人和白人妇女之间。 DNA甲基化为研究差异提供了独特的机会 种族/族裔之间不同的生活方式和社会文化条件可能表现为改变 在肿瘤DNA甲基化中，导致人群之间的表型差异。我们假设黑色 妇女将具有不同的甲基化模式组成或独特的肿瘤DNA甲基化特征 与白人妇女相比，生存率较差。为了限制疾病异质性的贡献，我们 将重点关注最常见和最致命的组织型，高级浆液卵巢癌 （HGSOC）。在239名黑人和478名HGSOC的白人女性中，将测量肿瘤DNA甲基化 使用Illumina甲基化阵列。弗里斯特，数据尺寸缩小方法将用于确定 肿瘤DNA甲基化特征与总体研究人群中的生存有关 在黑人和白人妇女中分别确定与 针对每个种族的特定成果以及在种族中共享的结果。这些签名将得到验证 在另外200名黑人和200名白人妇女中，有HGSOC。其次，前 有可能改变DNA甲基化态的诊断暴露（例如，诊断年龄，吸烟年龄 状态）和与结果相关的DNA甲基化特征将进行研究，以确定哪些因素可能 为预防策略提供信息。由于DNA甲基化是高度组织特异性的，因此DNA甲基化 肿瘤的特征是肿瘤中每个细胞的甲基化特征的加权混合物。 因此，在第三个目标中，我们将使用新细胞从肿瘤DNA甲基化数据中推断细胞组成 混合反卷积方法，并检查推断的细胞组成是否与死亡风险有关。 比较跨种群的DNA甲基化具有重要的应用，因为这项工作将推动 在代表性不足的种族少数群体中发现分子靶标的，有助于临床决策 制定并告知开发个性化疗法，以降低黑人妇女的死亡率和 最终减少了黑人和白人卵巢癌的生存差距。