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.

概括 结肠腺瘤占 CRC 癌前病变的 80-85%，并且可进展为 CRC。 这些早期病变大多数仍处于惰性早期状态，只有 5-10% 具有侵袭性并进展为 尽管最初提出腺瘤进展顺序主要是由序列驱动的。 结肠上皮细胞中基因突变和表观遗传改变的积累，基于越来越详细的研究 对结直肠癌特征性“致癌”变化的分析表明，这些变化显然是相同的 在惰性腺瘤甚至组织学正常的结肠上皮中也可以发现改变。 观察结果表明，仅 DNA 改变不足以驱动腺瘤的进展。 研究表明介导腺瘤进展的因素可源自组织学正常的结肠 组织“准备好”促进腺瘤进展为癌症。 由细胞自主和非自主机制驱动，“启动”结肠促进腺瘤 我们进一步追求的显着特征 “已启动”的结肠可以作为生物标志物来预测腺瘤进展为癌症的可能性。 目标 1A：通过执行以下操作来识别腺瘤进展的分子特征（“侵袭性”或“惰性”） 对一组独特的腺瘤进行多组学评估，并按明确的进展进行纵向跟踪 结果；AIM 1B：使用以下方法确定独立队列中腺瘤的“侵袭性”： 源自目标 1A 的进展分子特征。 目标 2：直接确定与腺瘤进展相关的“已启动”结肠的独特特征。 (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) 癌症驱动基因突变负担增加；(4) CRC 相关甲基化组改变， (5) 与结直肠癌相关的微生物群失调状态。 目标 3A：识别和评估基于 DNA 甲基化的组织生物标志物，以确定它们是否可以预测 使用高精度和灵敏的液滴数字 PCR 方法来降低侵袭性腺瘤发生的风险。 目标 3B：确定已启动结肠中的癌症驱动基因突变负担是否与侵袭性相关 使用高保真度和超深度测序方法检测腺瘤的发生。 该转化项目 1 将为早期病变和早期病变提供前所未有的高质量表征。 周围的启动结肠使其能够进展，该项目与该项目的专业知识相一致。 参与调查的人员、珍贵样本生物储存库的使用权以及 U54 提供的基础设施 项目 1 的重要性发现将在项目 2 和 3 及其他项目中进行功能性审查。 U54 项目，导致了一个迭代过程，以增进我们对腺瘤生物学和 开发用于预防结直肠癌的个性化生物标志物。