Molecular Risk Stratification for Colonoscopic Surveillance

 描述(申请人提供)：在包括PLCO试验在内的随机临床试验(RCT)中证实了结直肠癌(CRC)筛查的成功，这刺激了结肠镜检查的更多使用，结肠镜检查是美国首选的主要筛查方法。虽然筛查有助于最近结直肠癌发病率和死亡率的下降，但结肠镜检查的增加带来了新的临床挑战。首先，估计有8%-15%的结直肠癌发生在结肠镜检查后5年内，没有发现肿瘤(结肠镜检查阴性)，或者在所有可见的肿瘤被根除后出现。随着接受结肠镜检查的人口比例上升，这些肿瘤，即间歇性结直肠癌，将构成整个结直肠癌的更大负担。虽然一些间歇性癌可能是由于不理想的内窥镜技术，但很大一部分可能是由于与典型癌相比生物学上的差异而发生的。其次，结肠镜检查使用率的增加和由此导致的腺瘤的检测(公认的大多数结直肠癌的先兆)将刺激越来越多地使用监视结肠镜检查，或重复使用结肠镜检查对象的复发腺瘤。然而，监督结肠镜检查在临床实践中经常被不恰当地应用，高危受试者接受延迟监测，而低危受试者接受过度检测。根据风险适当调整监测的一个明显问题是，目前的指导方针直截了当且扩大化，主要得到了基于数十年前建立的病理分类的经验证据的支持。因此，为结肠镜检查改善腺瘤切除后个体风险分层的新方法是一个非常重要的未得到满足的需求。幸运的是，最近的努力，如癌症基因组图谱(TCGA)研究，极大地扩大了我们对结直肠癌基因组和分子特征的理解，并为应对这些新的临床挑战奠定了基础。我们的主要假设是，使用一组TCGA识别的CRC突变以及与间歇性CRC相关的新变化来表征意外切除的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，以获得最佳的内窥镜随访。为了解决这一假设，我们建议利用PLCO试验的独特组织资源，进行CRC的整个外显子组测序(WES)，以全面识别与Interval相关的特定体细胞基因组变化，而不是筛查检测到的CRC。这些改变，结合以前发现的与结直肠癌相关的更标准的分子异常，将在腺瘤中被询问，以确定它们与腺瘤复发的关系，并改进结肠镜监测间隔的定制。识别与间歇性结直肠癌和腺瘤复发相关的基因改变可能为如何通过改进结肠镜检查的风险分层更有效地预防间歇性结直肠癌提供新的见解，并有助于我们对肿瘤形态和进展的基本途径的理解。

 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.