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.

项目总结