Time lapse to cancer: defining transition from polyp to colorectal cancer (PQ14)

描述（由申请人提供）：结肠镜筛查是识别和清除结直肠癌（CRC）前驱病变的有效干预措施。自从采用结肠镜筛查以来的20年中，CRC在美国的发病率下降了30%，结肠镜筛查使医生能够检测和切除息肉，这是CRC的前驱病变。虽然结肠镜检查允许从业者观察息肉的内窥镜外观和病理学家的组织学评价，但这些诊断检查的措施不能定义息肉性质，这些性质预测哪些病变最有可能通过使息肉进展为癌症的分子事件转变。虽然大多数CRC是通过腺瘤性息肉的恶性转化而产生的，但只有5%的息肉进展为癌症。目前，最佳实践方案无法区分含有导致癌症的分子特征的息肉与可能保持良性的息肉。在回答挑衅性问题#14时，我们试图通过比较患有癌症的息肉与没有癌症的息肉来确定CRC的可定义属性。如果没有在分子水平上更好地了解息肉进展为癌症的生物学基础，医生和患者在没有关于预测息肉将转变为癌症的风险的因素的完整信息的情况下就决定了治疗方案。 这些研究旨在确定息肉的分子特征，这些特征可以区分给定病变的临床行为，以便在息肉进展为癌症的概率的背景下为个体患者确定最佳治疗机会。最近的研究利用基因组、mRNA和微小RNA转录组或甲基化组（GTM）的分子分析，试图通过研究来自不同个体的独立息肉和癌症来描绘癌发生的分子特征。本研究的第一个目的是比较在患有癌症邻近息肉的个体患者的息肉组织集合中发现的分子变化与在大小，组织学和异型增生程度方面相似的无癌息肉。第二个目标将通过在100组息肉上测试这些精细化的图谱来完善在目标一中发现的分子特征的图谱，以便将图谱集浓缩为负担得起的、准确的分子进展诊断面板。最后，这些特征将在一千组患者息肉中进行验证，以预测临床环境中的癌症进展风险。 该应用程序的目标是开发一组经济实惠、精致的GTM事件，以回答有关已开始转化为CRC的息肉与未开始转化的息肉中发生的分子事件的基本问题。这些研究解决了扩大知识基础的迫切需要，医生和患者可以在此基础上为有结肠直肠息肉转化和进展性恶性肿瘤风险的患者做出最佳病例实践决策，导致侵袭性转移性结肠直肠癌。 公共卫生相关性：在美国，CRC的发病率随着结肠镜检查的采用而下降，早期发现和切除息肉（前驱病变）可以阻止癌症的发展，但尽管如此，CRC仍然是美国癌症死亡的第二大原因。三分之一接受筛查结肠镜检查的人会有腺瘤性息肉，但不到5%的时间这些息肉发展成癌症。为什么一个息肉会发展成癌症，而另一个不会？在本申请中，我们将确定哪些遗传、mRNA表达和遗传甲基化模式将区分已经转化为癌症的息肉和尚未转化为癌症的息肉。

DESCRIPTION (provided by applicant): Colonoscopy screening is an effective intervention for identifying and removing precursor lesions for colorectal cancer (CRC). CRC has declined in incidence by 30% in the U.S. during the twenty years since adoption of colonoscopy screening that has enabled physicians to detect and remove polyps, the precursor lesion for CRC. While colonoscopy allows for observation of the endoscopic appearance of polyps by the practitioner and histological evaluation by pathologists, those measures of diagnostic scrutiny fall short of defining polyp properties that predict which lesions are most likely to transition through molecular events that commit a polyp to progress to cancer. Though the majority of CRC arises through malignant transformation of an adenomatous polyp, only 5% of those polyps progress to cancer. Currently, best practice protocols cannot discriminate between polyps containing molecular features leading to cancer from polyps that are likely to remain benign. In response to Provocative question #14, we seek to determine what the definable properties of CRC are, by comparing a polyp that has cancer from one that does not. Without a better understanding of the biological basis for polyp progression to cancer at the molecular level, physicians and patients approach decisions about treatment options without complete information about factors that predict the risk that polyps will transition to cancer. These studies propose to identify molecular features of polyps that differentiate the clinical behavior of given lesions so that optimal treatment opportunities can be determined for individual patients in the context of the probability that their polyps will progress to cancer. Recent studies utilizing molecular analysis f the genome, mRNA and micro RNA transcriptome or methylome (GTM) have attempted to depict the molecular features of carcinogenesis by studying independent polyps and cancer from different individuals. The first aim of this research will compare the molecular changes found in polyp tissue sets from individual patients with cancer adjacent polyps versus cancer-free polyps similar in terms of size, histology and degree of dysplasia. The second aim will refine the profiles of molecular features discovered in aim one by testing those refined profiles on a hundred sets of polyps in order to condense profile sets to affordable, accurate diagnostic panels of molecular progression. Finally, these profiles will be validated in a thousand sets of patient polyps to predict cancer progression risk in the clinical setting. The goals of this application are to develop an affordable, refined set of GTM events that answer fundamental questions about the molecular events that occur in polyps that have begun transformation to CRC compared to those that have not. These studies address a critical need to expand the base of knowledge upon which physicians and patients can make best case practice decisions for patients at risk for colorectal polyp transformation and progressive malignancy leading to invasive, metastatic colorectal cancer. PUBLIC HEALTH RELEVANCE: In the US, CRC incidence has declined with uptake in colonoscopy for early detection and removal of polyps, the precursor lesion, can stop a cancer from developing, but in spite of this, CRC remains the second leading cause of cancer death in the United States. One third of people who undergo screening colonoscopy will have adenomatous polyps, but less than 5% of the time do these polyps develop into cancer. Why does one polyp develop into cancer while another does not? In this application we will identify which genetic, mRNA expression and genetic methylation patterns will distinguish a polyp that has already transformed into cancer from one that has not.