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.

摘要 上皮性卵巢癌是女性中最致命的妇科恶性肿瘤， 确诊后存活五年。与白色相比，患有卵巢癌的黑人女性的生存率更低 妇女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 在获得护理或遵循指南的治疗方面存在差别。因此，它仍然是一个高度优先事项， 降低死亡率，提高生存率，尤其是黑人妇女。然而，大多数关于 卵巢癌来自白色妇女，这阻碍了发现对预后重要的新因素 在代表性不足的少数群体中。在这里，我们将利用流行病学，分子和结果数据， 研究卵巢癌生存差异的甲基化基础的成熟观察性研究 黑人和白色女人之间的区别DNA甲基化提供了一个独特的机会来研究差异， 不同种族/族裔群体之间不同的生活方式和社会文化条件可能表现为改变 肿瘤DNA甲基化，导致人群之间的表型差异。我们假设布莱克 女性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 与白色女性相比生存率更低。为了限制疾病异质性的贡献，我们 将集中在最常见和最致命的组织类型之一，高级别浆液性卵巢癌 （HGSOC）。在患有HGSOC的239名黑人和478名白色女性中，将测量肿瘤DNA甲基化 使用Illumina MethylationEPIC阵列。首先，将使用数据降维方法来确定 肿瘤DNA甲基化特征与整个研究人群的生存率相关， 分别在黑人和白色妇女中，确定与以下相关的差异甲基化区域： 每个种族特有的结果和跨种族共享的结果。这些签名将被验证 在另外200名黑人和200名白色女性HGSOC中。第二，前 具有改变DNA甲基化状态潜力的诊断暴露（例如，诊断时年龄，吸烟 状态）和结果相关的DNA甲基化特征将进行调查，以确定哪些因素可能 为预防战略提供信息。由于DNA甲基化是高度组织特异性的， 肿瘤的甲基化特征是肿瘤内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，我们将使用新的细胞从肿瘤DNA甲基化数据推断细胞组成。 混合物去卷积方法，并检查推断的细胞组成是否与死亡风险相关。 比较人群中的DNA甲基化具有重要的应用，因为这项工作将促进人类基因组的进化。 在代表性不足的少数族裔群体中发现分子靶点，帮助临床决策- 制定和宣传个性化治疗的发展，以降低黑人妇女的死亡率， 最终缩小患有卵巢癌的黑人和白色女性之间的生存差距。