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

摘要 结直肠癌(CRC)是由正常上皮细胞转化为正常上皮细胞的分子改变的结果 肿瘤对应物。实际上，所有的癌细胞都起源于腺瘤或锯齿状息肉，它们开始形成于 成年期，并导致6-7%的美国人口在80岁之前患上癌症。然而，由于30%-50%或 更多的人受到结肠息肉的影响，很明显，这些病变中的绝大多数不会 进展到结直肠癌，但更确切地说是良性增生性病变，而不是真正的癌前病变。这个 决定哪些息肉是“良性增生性疾病”，哪些是 “癌前状态”基本上是未知的。我们建议使用一种特殊而独特的临床 资源以确定潜在的基因改变概况、基因表达状态和/或 早期息肉的表观遗传状态决定着它的命运，使用体内生长速度作为衡量 可能是恶性的。允许我们进行这些研究的特殊和独特的资源是一个很大的 一系列人类大肠息肉，其体积生长模式已通过以下方式进行了系列评估 术前行CT结肠造影(CTC)。此外，CTC息肉数据的体积纹理分析， 可用于区分非肿瘤性增生性病变(增生性息肉)与腺瘤，将 与增长率相关。我们将关联整个外显子组测序、基因表达研究的结果， 以及具有观察到的基于CTC的体积生长模式的高密度甲基化阵列、织构分析 息肉组织学。 这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说(S)。我们之前已经表明， 许多突变和表观遗传变化在息肉形成的很早就出现了(大爆炸假说 肿瘤发生)而不是顺序的，并且最初的肿瘤轮廓决定息肉是否 癌前病变或良性病变。因此，一些息肉可能是“生来就是坏的”。在这个提案中，我们将测试这部小说 假设在息肉形成时建立的遗传、转录或表观遗传状态决定息肉是否 是良性增生性病变还是癌前状态。我们的具体目标是： 1.全面评估来自一大批大肠息肉患者的CTC数据，这些患者在活体内接受了 结肠镜切除前行连续CTC检查，以准确确定息肉生长速度和质地； 2.确定在肿瘤发生早期发生的突变或转录变化是否决定息肉 命运；以及 3.确定息肉的表观类型是否与生长行为和潜在的 成为一名中国儿童基金会成员。

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.