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

总结 结直肠癌（CRC）是将正常上皮细胞转化为其细胞的分子改变的结果。 肿瘤对应物。事实上，所有的CRC都来源于腺瘤或锯齿状息肉，它们开始形成于 成年后，并导致6%-7%的美国人口在80岁时患上癌症。然而，由于30-50%或 更多的人群受到结肠息肉的影响，很明显，这些病变中的绝大多数不 进展为CRC，而是良性增殖性病变，而不是真正的癌前病变。的 决定哪些息肉是“良性增殖性疾病”，哪些是 “恶化前状态”基本上是未知的。我们建议使用一种特殊而独特的临床 确定潜在的遗传改变谱、基因表达状态和/或 早期息肉的表观遗传状态决定其命运，使用体内生长速率作为 恶性潜能特殊和独特的资源，将使我们能够做这些研究是一个大的 一系列人类结肠直肠息肉，其体积生长模式已通过以下方法随时间连续评估： 切除前CT结肠造影（CTC）。此外，CTC息肉数据的体积纹理分析， 可用于区分非肿瘤增生性病变（增生性息肉）与腺瘤， 与增长率相关。我们将从全外显子组测序，基因表达研究， 和高密度甲基化阵列与观察到的基于CTC的体积生长模式，纹理分析 和息肉组织学。 这种对我们一系列良性和癌前息肉的“放射基因组学”分析将使我们能够检测一种 关于决定息肉命运的机制的创新假设。我们之前已经证明， 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，并且最初的肿瘤概况决定了息肉是否 癌前病变或良性病变。因此，有些珊瑚虫可能是“天生的坏”。在这个提案中，我们将测试小说 假设在息肉形成时建立的遗传、转录或表观遗传状态决定了息肉 是良性增生性病变或癌前状态。我们的具体目标是： 1.为了全面评估来自一个大型结直肠息肉患者队列的CTC数据， 在结肠镜切除前进行系列CTC，以准确确定息肉生长速率和质地; 2.为了确定是否发生在肿瘤发生早期的突变或转录变化决定了息肉的发生， 命运;以及 3.为了确定息肉的表观基因型是否与生长行为和潜在的 成为CRC。

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.