Deep molecular and cellular profiling of colorectal cancer tumor and immune microenvironment in Alaska Native people

阿拉斯加原住民结直肠癌肿瘤和免疫微环境的深入分子和细胞分析

• 批准号: 10651205
• 负责人: Jeroen R Huyghe
• 金额: $ 70.53万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-25 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651205
• 关键词: Address; Alaska; Alaska Native; Area; Biological; Biological Sciences; Biological Specimen Banks; Cancer Biology; Cancer Center; Cells; Cessation of life; Characteristics; Clinical; Collaborations; Colorectal Cancer; Colorectal Neoplasms; Communities; Data; Dedications; Development; Diagnosis; Disease Progression; Disparity; Ensure; Environmental Exposure; Epidemiology; Etiology; Evaluation; Formalin; Gene Expression; Genes; Genetic; Genetic Transcription; Germ-Line Mutation; Goals; Immune; Immune Evasion; Immune response; Incidence; Institutional Review Boards; Knowledge; Link; Medical Records; Molecular; Molecular Profiling; Monitor; Mutation; Native-Born; Not Hispanic or Latino; Outcome; Paraffin Embedding; Pathogenicity; Pathway interactions; Patients; Penetrance; Phenotype; Population; Prognostic Marker; Research; Research Priority; Resolution; Resources; Role; Sampling; Selection for Treatments; Somatic Mutation; Technology; The Cancer Genome Atlas; Time; Tissue Sample; Tribes; Tumor Tissue; Validation; Variant; Work; actionable mutation; biobank; cancer cell; cancer diagnosis; cancer health disparity; clinical decision-making; clinically actionable; colon cancer patients; colorectal cancer risk; colorectal cancer screening; digital; exome sequencing; experience; high risk; high risk population; improved; improved outcome; insight; long-standing disparities; member; molecular subtypes; mortality; nano-string; novel; novel therapeutic intervention; novel therapeutics; programs; risk variant; screening; spatial relationship; transcriptome; transcriptomic profiling; transcriptomics; translational goal; translational impact; translational potential; tribal health; tumor; tumor microenvironment; tumor-immune system interactions; tumorigenesis

PROJECT SUMMARY Alaska Native people have the highest incidence and mortality rates of colorectal cancer (CRC) globally, with rates that are more than double those observed in the general U.S. population (incidence: 89.0 vs. 38.6/100,000; mortality: 39.6/100,000 vs. 13.8/100,000). These high rates cannot be explained by access to screening, as dedicated efforts to increase CRC screening have resulted in screening rates in Alaska Native people that are comparable to the US average. These disparities have persisted for over 40 years and are of noted concern to community members and Tribal health leaders alike, making this a priority research area for Alaska Native people. A key knowledge gap is the lack of sizable and comprehensive studies characterizing the molecular features of colorectal tumors in Alaska Native patients. Accordingly, we propose an integrative approach to better understand CRC tumorigenesis and molecular subtypes in this high-risk population, and to evaluate whether various tumor and tumor microenvironment features contribute to disease progression. Specifically, we aim to deeply characterize the mutational, transcriptional, and cellular landscapes of CRC tumors and their immune microenvironments in 500 Alaska Native patients and link these characteristics to CRC-specific mortality. We will build on our existing collaboration between the Alaska Native Tribal Health Consortium (ANTHC) and the Fred Hutchinson Cancer Center. We will capitalize on ANTHC’s unique biorepository (linkable to comprehensive medical records) that contains tumor tissue samples of the majority of Alaska Native CRC patients diagnosed in Alaska. Pilot data generated using biospecimens from this resource and utilizing the same platforms as proposed here demonstrate high-quality data and ensure that IRB and tribal approvals are in place to enable rapid execution of the proposed work. To identify clinically meaningful population differences, we will compare molecular profiles with those from non-Hispanic White CRC patients using available data. In Aim 1, we will perform whole-exome sequencing of CRC tumors and paired normal samples to identify driver genes and clinically actionable mutations particularly relevant to the Alaska Native population. To gain etiological insight, we will analyze mutational signatures that may be linked to environmental exposures and identify germline mutations in high-penetrance CRC risk genes to investigate their role in the increased CRC risk in Alaska Native people. In Aim 2, we will apply two complementary cutting-edge spatial profiling technologies to fully characterize the tumoral immune response and discover mechanisms of immune evasion. We will perform spatial whole transcriptome profiling of CRC tumors using Nanostring’s GeoMx Digital Spatial Profiling technology. We will use Akoya Biosciences’ PhenoCycler platform for spatially resolved single immune cell phenotyping. We expect that insights gained through this work can inform the development of high-value, novel therapeutic strategies. In Aim 3, we will leverage these molecular data to develop novel predictors of CRC-specific mortality that could help guide clinical decision making, improve outcomes, and reduce long-standing disparities.

项目概要 阿拉斯加原住民的结直肠癌 (CRC) 发病率和死亡率是全球最高的，其中 是美国普通人群中观察到的比率的两倍多（发生率：89.0 vs. 38.6/100,000； 死亡率：39.6/100,000 vs. 13.8/100,000）。 致力于增加 CRC 筛查的努力已导致阿拉斯加原住民的筛查率有所提高， 这些差异已经持续了 40 多年，并且引起了人们的高度关注。 社区成员和部落健康领袖等，使之成为阿拉斯加原住民的优先研究领域 一个关键的知识差距是缺乏大规模和全面的分子特征研究。 因此，我们提出了一种更好的综合方法。 该高危人群中的 CRC 肿瘤发生和分子亚型，并评估是否 具体来说，我们的目标是各种肿瘤和肿瘤微环境特征有助于疾病进展。 深入表征 CRC 肿瘤及其免疫系统的突变、转录和细胞景观 研究人员对 500 名阿拉斯加原住民患者的微环境进行了研究，并将这些特征与 CRC 特异性死亡率联系起来。 将建立在阿拉斯加原住民部落健康联盟 (ANTHC) 和 我们将利用 ANTHC 独特的生物样本库（可链接到综合性的生物样本库）。 医疗记录）包含大多数阿拉斯加原住民 CRC 患者的肿瘤组织样本 阿拉斯加。使用来自该资源的生物样本并利用与提议的相同的平台生成的试点数据。 在这里展示高质量的数据并确保 IRB 和部落批准到位，以实现快速 为了确定具有临床意义的人群差异，我们将进行比较。 在目标 1 中，我们将使用现有数据对非西班牙裔白人 CRC 患者进行分子谱分析。 对 CRC 肿瘤和配对正常样本进行全外显子组测序，以确定驱动基因和 与阿拉斯加原住民特别相关的临床可操作突变为了获得病因学见解， 我们将分析可能与环境暴露有关的突变特征并识别种系 高外显率 CRC 风险基因突变，以研究其在阿拉斯加原住民 CRC 风险增加中的作用 在目标 2 中，我们将应用两种互补的尖端空间分析技术来充分表征。 我们将进行空间整体研究，研究肿瘤的免疫反应并发现免疫逃避的机制。 我们将使用 Nanostring 的 GeoMx 数字空间分析技术对 CRC 肿瘤进行转录组分析。 我们预计 Akoya Biosciences 的 PhenoCycler 平台可用于空间分辨单免疫细胞表型分析。 通过这项工作获得的见解可以为 In Aim 的高价值、新颖的治疗策略的开发提供信息。 3，我们将利用这些分子数据开发新的 CRC 特异性死亡率预测因子，这可能有助于 指导临床决策、改善结果并减少长期存在的差异。