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.

项目摘要 胰腺导管腺癌（PDAC）是一种致命疾病，对当前的治疗策略难治性 部分原因是化学抗性的自适应机制。种族健康差异也混淆了治疗 和照顾这些患者。黑人的PDAC发病率明显更高，生存率降低 与白人和拉丁裔/西班牙裔（L/H）相比，即使在社会经济状况和肿瘤阶段也是如此 受控。因此，它可能不同的种族群体在PDAC肿瘤中表现出独特的分子特征 这导致了这些健康差异。区分PDAC肿瘤的分子特征 种族群体有可能确定克服差异所需的新型治疗靶标。的确， 描述肺，乳腺癌和前列腺癌健康差异的基本分子基础已导致 治疗进步和改善患者预后。 PDAC的类似突破是可能的，并且 这种致命的疾病需要，但是尚未充分探索这一研究领域。我们确定了4 可以区分PDAC的不同亚型（代谢，祖细胞状，增生和炎症性） 使用定量质谱数据的多元分析。这些PDAC亚型可预测 治疗反应，但这尚未在种族多样化的人群中进行分析。我们已经检查了 使用定量质谱法的原代PDAC肿瘤的蛋白质组织，并鉴定出独特的蛋白质 黑人，L/H和白人的签名。在黑人患者的PDAC肿瘤中，我们观察到特征一致 PDAC的炎症亚型的特征是炎症微环境和 对化学疗法的抗性。因此，种族可能会影响亚型和黑人优先 发展更具侵略性和治疗难治性炎症亚型。但是，基础遗传 尚未检查与PDAC亚型规范相关的变体。朝着这个目标，我们的项目将 利用我们所有的数据库来识别多样的队列胰腺癌患者的变体并评估 与PDAC肿瘤发生相关的特定基因集，包括酒精反应基因和差异 在源自黑色的PDAC中表达蛋白质。此外，我们将执行发现GWAS分析 识别与我们所有人队列中与PDAC开发相关的变体，并检查其预测功能 选定的PDAC亚型规范基因的后果。这些目标的成功完成了 在此建议中，有可能提高我们对PDAC亚型规范驱动因素的理解， 可以通过优化治疗策略来开发以改善患者的总体生存。