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癌性病变的80-85％，可以发展为CRC。但是， 这些早期病变中的大多数仍处于懒惰的早期状态，只有5-10％的人具有侵略性，并进步为 尽管最初提出腺瘤进展序列主要由序列驱动 基于越来越详细的基因突变和表观遗传改变的积累 对CRC表征的“引起癌症”变化的分析，显然是相同的 也可以在懒惰的腺瘤甚至组织学正常结肠上皮中发现改变。这些 观察结果表明，单独的DNA改变不足以驱动腺瘤进展。新兴 研究表明，介导腺瘤进展的因素可以从组织学正常结肠中得出 组织“底漆”以促进腺瘤发展为癌症。我们假设腺瘤的进展是 由细胞自主和非自治机制驱动，“底漆”结肠促进了腺瘤 通过提供允许的组织环境进行进展。我们进一步假设 可以开发“底漆”结肠作为生物标志物，以预测腺瘤发展为癌症的可能性。 AIM 1A：通过执行腺瘤进展的分子特征（“攻击性”或“懒惰”） 对腺瘤的独特集合进行的Mutli-Omics评估，纵向进行了定义的进展 结果； AIM 1B：使用使用 源自AIM 1A的进展的分子特征。 目标2：直接确定与腺瘤进展相关的“底漆”结肠的不同特征。 （1）增加感觉成纤维细胞负荷和相关的SASP因子表达； （2）致癌免疫 微环境； （3）癌症驱动基因突变伯恩的增加； （4）CRC相关的甲基团改变， （5）不植物CRC相关的微生物组状态。 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预测 使用高度精确且敏感的液滴数字PCR方法发生攻击性腺瘤的风险。 AIM 3B：确定癌症驱动基因突变是否与侵略性的结肠伴侣中 腺瘤使用高保真和超深测序方法发生。 这个翻译项目1将为早期病变和 周围的底漆使其进展。该项目与 涉及的调查人员，获得珍贵样品生物库的访问和U54提供的基础设施 机制。项目1的显着性发现将在项目2和3和其他项目中进行功能询问 U54项目，导致迭代过程，以促进我们对腺瘤生物学和 开发用于预防CRC的个性化生物标志物。