Molecular Risk Stratification for Colonoscopic Surveillance

 描述（由申请人提供）：在随机临床试验（RCT）（包括PLCO试验）中，结直肠癌（CRC）筛查的成功已经证明，结肠镜检查的使用越来越多，结肠镜检查是美国首选的主要筛查手段。尽管筛查有助于近期CRC发病率和死亡率的下降，但结肠镜检查的使用越来越多，这带来了新的临床挑战。首先，估计8-15%的CRC发生在结肠镜检查未检测到肿瘤（阴性结肠镜检查）的5年内或在所有可见的肿瘤已被根除后。随着接受结肠镜检查的人群比例的增加，这些肿瘤（称为间隔期CRC）将构成整体CRC的更大负担。尽管一些间期CRC可能是由于次优内镜技术所致，但相当大一部分可能是由于与典型CRC相比的生物学差异所致。其次，结肠镜检查使用的增加和由此检测到的腺瘤（大多数CRC的公认前兆）将刺激越来越多地使用监测性结肠镜检查或重复结肠镜检查监测受试者的复发性腺瘤。然而，监测结肠镜检查在临床实践中经常被不恰当地应用，高风险受试者接受延迟的监测，而低风险受试者接受过度的测试。根据风险适当调整监测的一个突出问题是，目前的指南是生硬和广泛的，主要是基于几十年前建立的病理分类的经验证据支持。因此，新的方法，以改善个体的风险分层后切除腺瘤结肠镜监测是一个非常显着的未满足的需求。幸运的是，最近的努力，如癌症基因组图谱（TCGA）研究，极大地扩展了我们对CRC基因组和分子特征的理解，并为解决这些新的临床挑战奠定了基础。我们的总体假设是，使用一组TCGA鉴定的CRC突变以及与间隔CRC相关的新改变来表征事件切除腺瘤的基因组特征，可以更好地评估复发风险并对患者进行分层，以进行最佳内镜随访。为了解决这一假设，我们建议使用PLCO试验的独特组织资源，对CRC进行全外显子组测序（WES），以全面鉴定与间隔相关的特定体细胞基因组改变，而不是筛查检测到的CRC。这些改变，结合更标准的，以前确定的与CRC相关的分子异常，将在腺瘤中进行查询，以确定其与腺瘤复发的相关性，并改善结肠镜监测间隔的定制。鉴定与间隔期CRC和腺瘤复发相关的遗传改变可能为如何通过改善结肠镜检查的风险分层更有效地预防间隔期CRC提供新的见解，并为我们了解肿瘤形态和进展的基本途径提供信息。

 DESCRIPTION (provided by applicant): The demonstrated success of colorectal cancer (CRC) screening in randomized clinical trials (RCT), including the PLCO Trial, has spurred increased use of colonoscopy, which is the preferred primary means of screening in the U.S. Although screening has contributed to recent declines in CRC incidence and mortality, the increasing utilization of colonoscopy poses new clinical challenges. First, an estimated 8-15% of CRC arise within 5 years of a colonoscopy without detection of neoplasia (negative colonoscopy) or after all visible neoplasia has been eradicated. As the proportion of the population undergoing colonoscopy rises, these tumors, known as interval CRC, will comprise a greater burden of overall CRC. Although some interval CRCs may be due to suboptimal endoscopic technique, a substantial portion likely develops due to differences in biology compared to typical CRCs. Second, the increase in colonoscopy utilization and resulting detection of adenomas, the acknowledged precursor of most CRC, will stimulate increasing use of surveillance colonoscopy, or repeated colonoscopic monitoring of subjects for recurrent adenomas. However, surveillance colonoscopy is often improperly applied in clinical practice, with higher risk subjects undergoing delayed surveillance, and lower risk subjects undergoing excessive testing. A glaring problem in properly tailoring surveillance to risk is that current guidelines are blunt and expansive, supported by largely empirical evidence based on pathologic classifications established decades ago. Thus, novel approaches to improve risk stratification of individuals after resection of adenoma for colonoscopic surveillance is a highly significant unmet need. Fortunately, recent efforts such as The Cancer Genome Atlas (TCGA) study have vastly expanded our understanding of the genomic and molecular features of CRC and have laid the foundation for addressing these new clinical challenges. Our overarching hypothesis is that characterization of genomic features of incident resected adenomas using a panel of TCGA-identified CRC-mutations as well as novel alterations associated with interval CRC can better assess recurrence risk and stratify patients for optimal endoscopic follow-up. To address this hypothesis, we propose to conduct, using the unique tissue resources of the PLCO Trial, whole exome sequencing (WES) of CRCs to comprehensively identify specific somatic genomic alterations associated with interval as opposed to screen-detected CRC. These alterations, combined with more standard, previously identified molecular abnormalities associated with CRC, will be queried in adenomas to determine their association with adenoma recurrence and improve tailoring of colonoscopic surveillance intervals. Identification of genetic alterations associated with interval CRC and recurrence of adenoma may provide new insights into how to more effectively prevent interval CRC through improved risk stratification for colonoscopy and inform our understanding of pathways fundamental to tumor morphology and progression.