(PQ6) Radiogenomics of colorectal polyps to assess benign proliferative vs. premalignant states.

(PQ6) 结直肠息肉的放射基因组学，以评估良性增殖与癌前状态。

• 批准号: 9761849
• 负责人: William Mallory Grady
• 金额: $ 67.82万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761849
• 关键词: Address; Adenomatous Polyps; Adult; Affect; Age-Years; Behavior; Benign; Birth; Chemoprevention; Clinical; Clone Cells; Colon; Colonic Polyps; Colorectal Cancer; Colorectal Polyp; Computed Tomographic Colonography; DNA Methylation; Data; Disease; Epigenetic Process; Epithelial Cells; Excision; Gene Expression; Genetic; Genetic Transcription; Goals; Growth; Histology; Human; Hyperplastic Polyp; Individual; Lead; Lesion; Malignant - descriptor; Malignant Neoplasms; Measures; Methods; Methylation; Molecular; Mutation; Mutation Analysis; Patients; Pattern; Polyps; Population; Precancerous Conditions; Premalignant; Radiogenomics; Resected; Resources; Risk Assessment; Series; Surrogate Endpoint; Testing; Texture; Time; Work; actionable mutation; adenoma; base; cancer genetics; cohort; colon tumorigenesis; colorectal cancer prevention; colorectal cancer risk; density; exome; exome sequencing; genetic profiling; genome-wide; improved; in vivo; innovation; insight; interest; malignant state; molecular subtypes; neoplastic; novel; theories; time use; tumor; tumorigenesis; virtual

SUMMARY Colorectal cancer (CRC) is consequence of molecular alterations transforming normal epithelial cells into their neoplastic counterparts. Virtually, all CRCs derive from adenomas or serrated polyps, which begin forming in adulthood, and lead to cancer in 6-7% of the U.S. population by 80 years of age. However, since 30-50% or more of the population is affected by colon polyps, it is apparent that the vast majority of these lesions do not progress to CRC, but rather are benign proliferative lesions and not truly premalignant lesions. The molecular mechanisms that dictate which polyps are “benign proliferative disease” and which are “premalignant states” are essentially unknown. We propose to use an exceptional and unique clinical resource to determine whether the underlying genetic alteration profile, gene expression status, and/or epigenetic state of an early polyp governs its fate, using in vivo growth rate as a surrogate measure of malignant potential. The exceptional and unique resource that will permit us to do these studies is a large series of human colorectal polyps whose volumetric growth patterns have been serially assessed over time by CT colonography (CTC) prior to resection. In addition, volumetric textural analysis of CTC polyp data, which can be used to distinguish non-neoplastic proliferative lesions (hyperplastic polyps) from adenomas, will be correlated with growth rates. We will correlate results from whole exome sequencing, gene expression studies, and high-density methylation arrays with the observed CTC-based volumetric growth patterns, textural analysis and polyp histology. This “radiogenomic” analysis of our series of benign and premalignant polyps will then allow us to test an innovative hypothesis about the mechanism(s) that determines a polyp’s fate. We have previously shown that many mutations and epigenetic alterations arise very early in polyp formation (the “Big Bang” hypothesis of tumorigenesis) rather than sequentially, and that the initial tumor profile governs whether the polyp is premalignant or benign. Thus, some polyps might be “born to be bad”. In this proposal, we will test the novel hypothesis that the genetic, transcriptional, or epigenetic state established at polyp formation dictates if a polyp is a benign proliferative lesion or a premalignant state. Our SPECIFIC AIMS are: 1. To fully assess CTC data from a large cohort of patients with colorectal polyps that were followed in vivo by serial CTC prior to colonoscopic resection to accurately establish polyp growth rates and texture; 2. To determine whether mutations or transcriptional changes that occur early in tumorigenesis dictate polyp fate; and 3. To determine whether the epigenotype of a polyp correlates with growth behavior and the potential to become a CRC.

概括 结直肠癌（CRC）是分子改变将正常上皮细胞转变为正常上皮细胞的结果。 肿瘤对应物。事实上，所有结直肠癌都源自腺瘤或锯齿状息肉，它们开始形成于 成年后，到 80 岁时，6-7% 的美国人口会患上癌症。然而，由于 30-50% 或 更多的人受到结肠息肉的影响，显然绝大多数这些病变并没有 进展为结直肠癌，而是良性增殖性病变，而不是真正的癌前病变。这 决定哪些息肉是“良性增殖性疾病”以及哪些是“良性增殖性疾病”的分子机制 “癌前状态”基本上是未知的。我们建议使用特殊且独特的临床 确定潜在的遗传改变概况、基因表达状态和/或 早期息肉的表观遗传状态决定其命运，使用体内生长率作为替代指标 恶性潜能。使我们能够进行这些研究的特殊而独特的资源是巨大的 系列人类结直肠息肉，其体积生长模式已随着时间的推移进行了连续评估 切除前 CT 结肠成像 (CTC)。此外，CTC 息肉数据的体积纹理分析， 可用于区分非肿瘤性增生性病变（增生性息肉）与腺瘤， 与增长率相关。我们将把全外显子组测序、基因表达研究的结果关联起来， 和高密度甲基化阵列，具有观察到的基于 CTC 的体积生长模式、结构分析 和息肉组织学。 对我们一系列良性和癌前息肉的“放射基因组”分析将使我们能够测试 关于决定息肉命运的机制的创新假设。我们之前已经证明了 许多突变和表观遗传改变在息肉形成的早期就出现了（“大爆炸”假说） 肿瘤发生）而不是顺序，并且初始肿瘤特征决定息肉是否是 癌前或良性。因此，有些息肉可能“生来就是坏的”。在这个提案中，我们将测试小说 假设息肉形成时建立的遗传、转录或表观遗传状态决定了息肉是否 是良性增殖性病变或癌前状态。我们的具体目标是： 1. 全面评估一大群结直肠息肉患者的 CTC 数据，并进行体内随访 在结肠镜切除术之前进行系列 CTC，以准确确定息肉的生长速度和质地； 2. 确定肿瘤发生早期发生的突变或转录变化是否决定息肉 命运;和 3. 确定息肉的表观基因型是否与生长行为及其潜力相关 成为CRC。