Pancreatic cancer variant analysis of the All of Us cohort

我们所有人队列的胰腺癌变异分析

• 批准号: 10660291
• 负责人: Robert E. Lewis
• 金额: $ 11.51万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10660291
• 关键词: Acinar Cell; Address; Affect; African; African American; Alcohol consumption; Alcohols; Black Populations; Black race; Characteristics; Chemoresistance; Classification; Clinical; Clinical Management; Code; Communities; Data; Data Set; Databases; Demographic Survey; Development; Disease; Epigenetic Process; Ethnic Origin; Evaluation; Exhibits; Face; Future; Genes; Genetic Transcription; Genetic Variation; Genomic Segment; Goals; Hispanic; Hispanic Populations; Impairment; Incidence; Inflammatory; KRAS2 gene; Latino; Latino Population; Latinx; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Mass Spectrum Analysis; Metabolic; Minority; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Multivariate Analysis; Mutation; Oncogenes; Outcome; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Polycomb; Population Heterogeneity; Prediction of Response to Therapy; Proteins; Proteome; Proteomics; Publishing; Race; Refractory; Regulation; Repressor Proteins; Research; Resistance; Sampling; Socioeconomic Status; Therapeutic; Time; Transcript; Tumor stage; Untranslated RNA; Validation; Variant; Work; aggressive therapy; black patient; cBioPortal; cancer subtypes; cancer type; cell dedifferentiation; chemotherapy; clinically relevant; cohort; differential expression; ethnic health disparity; experience; experimental study; genetic variant; genome sequencing; genome wide association study; genomic variation; health disparity; improved; in silico; malignant breast neoplasm; member; molecular marker; molecular subtypes; new therapeutic target; pancreatic cancer patients; pancreatic tumorigenesis; progenitor; prognostic of survival; racial and ethnic; racial disparity; racial diversity; racial health disparity; socioeconomics; survival outcome; targeted treatment; treatment optimization; treatment strategy; tumor; tumorigenesis; whole genome

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is refractory to current treatment strategies due in part to adaptive mechanisms of chemoresistance. Racial health disparities also confound the treatment and care of these patients. Blacks have significantly higher incidence rates of PDAC and decreased survival times compared to Whites and Latino/Hispanics (L/H) even after socioeconomic status and tumor stages are controlled. Therefore, it is likely different racial groups exhibit unique molecular characteristics in PDAC tumors that contribute to these health disparities. The molecular characteristics that distinguish PDAC tumors between racial groups have the potential to identify novel therapeutic targets required to overcome the disparities. Indeed, delineating the underlying molecular basis for health disparities in lung, breast and prostate cancers has led to therapeutic advancements and improved patient outcomes. Similar breakthroughs for PDAC are possible and needed for this deadly disease, but this field of research has not yet been adequately explored. We identified 4 distinct subtypes of PDAC (Metabolic, Progenitor-like, Proliferative, and Inflammatory) that can be distinguished using multivariate analysis of quantitative mass spectrometry data. These PDAC subtypes are predictive of therapeutic response, but this has not yet been analyzed in a racially diverse population. We have examined the proteomes of primary PDAC tumors using quantitative mass spectrometry and identified unique protein signatures for Blacks, L/H, and Whites. In PDAC tumors from Black patients, we observed features consistent with the Inflammatory subtype of PDAC, which is characterized by an inflammatory microenvironment and resistance to chemotherapy. Therefore, it is possible that race influences subtype and Blacks could preferentially develop the more aggressive and treatment refractory Inflammatory subtype. However, the underlying genetic variants associated with PDAC subtype specification have not been examined. Toward this goal, our project will utilize the All of Us database to identify variants in a diverse cohort pancreatic cancer patients and evaluate specific gene sets associated with PDAC tumorigenesis, including alcohol responsive genes, and differentially expressed proteins in PDACs originating in Blacks. In addition, we will perform a discovery GWAS analysis to identify variants associated with PDAC development in the All of Us cohort and examine their predicted functional consequences in selected PDAC subtype specification genes. The successful completion of these aims outlined in this proposal has the potential to improve our understanding of the drivers of PDAC subtype specification, which could be developed to improve overall patient survival by optimizing treatment strategies.

项目概要 胰腺导管腺癌（PDAC）是一种致命疾病，目前的治疗策略难以治愈 部分原因是化学耐药性的适应性机制。种族健康差异也使治疗变得混乱 以及对这些患者的护理。黑人的 PDAC 发病率明显较高，且生存率较低 与白人和拉丁裔/西班牙裔 (L/H) 相比，即使社会经济状况和肿瘤分期已确定 受控。因此，不同种族群体在 PDAC 肿瘤中可能表现出独特的分子特征 造成这些健康差异的因素。区分 PDAC 肿瘤的分子特征 种族群体有潜力确定克服差异所需的新治疗目标。的确， 描述肺癌、乳腺癌和前列腺癌健康差异的潜在分子基础已导致 治疗的进步和患者治疗效果的改善。 PDAC 也可能取得类似的突破 这种致命疾病所需的药物，但这一研究领域尚未得到充分探索。我们确定了 4 可区分的不同 PDAC 亚型（代谢型、祖细胞型、增殖型和炎症型） 使用定量质谱数据的多变量分析。这些 PDAC 亚型可预测 治疗反应，但这尚未在不同种族的人群中进行分析。我们已经检查了 使用定量质谱分析原发性 PDAC 肿瘤的蛋白质组并鉴定出独特的蛋白质 黑人、左翼/右翼和白人的签名。在黑人患者的 PDAC 肿瘤中，我们观察到一致的特征 PDAC 的炎症亚型，其特征是炎症微环境和 对化疗的抵抗力。因此，种族可能会影响亚型，黑人可以优先选择 开发更具侵袭性和难治性的炎症亚型。然而，潜在的遗传 尚未检查与 PDAC 亚型规范相关的变体。为了实现这一目标，我们的项目将 利用 All of Us 数据库来识别不同队列胰腺癌患者的变异并进行评估 与 PDAC 肿瘤发生相关的特定基因集，包括酒精反应基因，以及差异 在源自黑人的 PDAC 中表达蛋白质。此外，我们将进行发现 GWAS 分析 识别与“我们所有人”队列中 PDAC 发育相关的变异，并检查其预测的功能 选定的 PDAC 亚型规范基因的后果。成功完成这些概述的目标 该提案有可能提高我们对 PDAC 子类型规范驱动因素的理解， 可以通过优化治疗策略来提高患者的总体生存率。