Comprehensive atlas of advanced adenomas and their surrounding primed colon: A multi-omics evaluation and clinical impact assessment

晚期腺瘤及其周围的结肠的综合图谱：多组学评估和临床影响评估

• 批准号: 10519074
• 负责人: William Mallory Grady
• 金额: $ 67.95万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10519074
• 关键词: Aberrant DNA Methylation; Architecture; Atlases; Biological; Biological Markers; Biological Models; Biology; Cells; Clinical; Collection; Colon; Colonic Adenoma; Complex; DNA Methylation; DNA Sequence Alteration; Development; Ecosystem; Environment; Epigenetic Process; Epithelial; Epithelial Cells; Evaluation; Fibroblasts; Fostering; Gene Mutation; Gnotobiotic; Histologic; Indolent; Infrastructure; Lesion; Malignant Neoplasms; Mediating; Methods; Microbe; Modeling; Molecular Profiling; Monitor; Oncogenic; Organism; Outcome; Patients; Phenotype; Play; Process; Research Personnel; Resolution; Resources; Risk; Role; Sampling; Testing; Tissues; adenoma; base; biobank; cancer prevention; cell type; cohort; colon cancer patients; colorectal cancer prevention; colorectal cancer screening; deep sequencing; digital; driver mutation; dysbiosis; gut microbiome; gut microbiota; insight; methylation pattern; methylome; microbiome; multiple omics; premalignant; programs; prospective; recruit; risk stratification; senescence; tissue biomarkers; tumor; tumor-immune system interactions

SUMMARY Colon adenomas account for 80-85% of the CRC precancerous lesions and can progress to CRC. Yet, the majority of these early lesions remain in an indolent early state, and only 5-10% are aggressive and progress to CRC. Although the adenoma progression sequence was initially proposed to be driven mainly by the serial accumulation of gene mutations and epigenetic alterations in colon epithelial cells, based on increasingly detailed analyses of the ‘cancer-causing’ alterations that characterize CRC, it has becoming apparent that these same alterations can also be found in indolent adenomas and even in the histologically normal colon epithelium. These observations indicate that DNA alterations alone are not sufficient to drive adenoma progression. Emerging studies indicate that factors that mediate adenoma progression can be derived from histologically normal colon tissue ‘primed’ to foster adenoma progression into cancer. We hypothesize that the adenoma progression is driven by both cell-autonomous and non-autonomous mechanisms and the ‘primed’ colon promotes adenoma progression by providing a permissive tissue environment. We further hypothesize that the distinct features of a ‘primed’ colon may be developed as biomarkers to predict the likelihood of adenoma progression to cancer. AIM 1A: To identify molecular signatures of adenoma progression (‘aggressive’ or ‘indolent’) by performing a mutli-omics evaluation of a unique collection of adenomas followed longitudinally with defined progression outcomes; AIM 1B: To determine the ‘aggressiveness’ of adenomas in an independent cohort using the molecular signature of progression derived from Aim 1A. AIM 2: To directly determine the distinct features of a ‘primed’ colon that associate with adenoma progression. (1) increased senescent fibroblast load and associated SASP factor expression; (2) oncogenic immune microenvironment; (3) increased cancer driver gene mutation burden; (4) altered CRC associated methylome, and (5) the dysbiotic CRC-associated microbiome state. AIM 3A: To identify and evaluate DNA methylation-based tissue biomarkers to determine whether they predict the risk of aggressive adenoma occurrence using a highly precise and sensitive droplet digital PCR method. AIM 3B: To determine if the cancer driver gene mutation burden in the primed colon associates with aggressive adenoma occurrence using a high fidelity and ultra-deep sequencing method. This translational Project 1 will provide an unprecedented high-quality characterization of the early lesion and the surrounding primed colon that enables its progression. This project aligns with the expertise of the investigators involved, the access to precious sample biorepositories and the infrastructure provided by the U54 mechanism. The significance findings from Project 1 will be functionally interrogated in Project 2&3 and other U54 projects, leading to an iterative process to advance our understanding of the adenoma biology and the development of personalized biomarkers for CRC prevention.

摘要 结肠腺瘤占结直肠癌癌前病变的80%-85%，可进展为结直肠癌。然而， 这些早期病变大多数仍处于惰性早期状态，只有5%-10%的病变具有侵袭性并进展为 CRC。尽管腺瘤进展序列最初被认为主要由序列驱动 结肠上皮细胞中基因突变和表观遗传学改变的积累，基于越来越详细的 根据对CRC特征的“致癌”改变的分析，越来越明显的是，这些相同的 在惰性腺瘤中也可以发现改变，甚至在组织学上正常的结肠上皮中也可以发现改变。这些 观察表明，仅有DNA改变不足以驱动腺瘤的进展。新兴 研究表明，介导腺瘤进展的因子可以来自组织学上正常的结肠。 组织为促进腺瘤进展为癌症做好了准备。我们假设腺瘤的进展是 由细胞自主机制和非自主机制驱动，并促进结肠腺瘤 通过提供允许的组织环境来促进进展。我们进一步假设， “预置”的结肠可能被开发为预测腺瘤进展为癌症的可能性的生物标志物。 目标1A：通过进行一项研究，确定腺瘤进展的分子特征(侵袭性或惰性)。 对一组独特的纵向进展的腺瘤进行多组学评估 结果：目的1B：确定腺瘤在独立队列中的侵袭性 从目标1A派生的级数的分子签名。 目的2：直接确定与腺瘤进展相关的“预置”结肠的明显特征。 (1)衰老成纤维细胞负荷和相关SASP因子表达增加；(2)致癌免疫 微环境；(3)增加癌症驱动基因突变负担；(4)改变CRC相关甲基组， (5)与CRC相关的微生物群态。 目的3A：识别和评估基于DNA甲基化的组织生物标记物，以确定它们是否可以预测 使用高精度和灵敏的水滴数字聚合酶链式反应方法预测侵袭性腺瘤发生的风险。 目的3B：确定启动结肠中的癌症驱动基因突变负荷是否与侵袭性有关 腺瘤的发生使用高保真和超深度测序方法。 此翻译项目1将提供对早期病变的前所未有的高质量描述，并 周围有启动的结肠，使其得以进展。这一项目与 所涉及的调查人员、对珍贵样本生物库的访问以及U54提供的基础设施 机制。项目1的重要性调查结果将在项目2和3以及其他项目中进行功能询问 U54项目，导致了一个迭代的过程，以促进我们对腺瘤生物学和 用于预防结直肠癌的个性化生物标志物的开发。