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。自采用结肠镜筛查使医生能够发现并切除息肉（结直肠癌的前体病变）以来，美国结直肠癌的发病率在20年内下降了30%。虽然结肠镜检查允许医生观察息肉的内窥镜外观，病理学家进行组织学评估，但这些诊断检查的措施不足以定义息肉的特性，无法预测哪些病变最有可能通过分子事件转变为癌症。虽然大多数结直肠癌是由腺瘤性息肉的恶性转化引起的，但只有5%的息肉发展为癌症。目前，最佳实践方案不能区分含有导致癌症的分子特征的息肉和可能保持良性的息肉。为了回答挑衅性问题14，我们试图通过比较患有癌症的息肉和未患癌症的息肉来确定CRC的可定义属性。如果在分子水平上对息肉发展为癌症的生物学基础没有更好的了解，医生和患者在决定治疗方案时就没有完整的信息来预测息肉转变为癌症的风险。这些研究提出确定区分特定病变临床行为的息肉分子特征，以便在其息肉发展为癌症的可能性的背景下，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RNA转录组或甲基组（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述癌变的分子特征。本研究的第一个目的是比较个体癌旁息肉患者与无癌息肉患者在大小、组织学和发育不良程度上相似的息肉组织组中的分子变化。第二个目标将细化目标一中发现的分子特征，通过在100组息肉上测试这些改进的特征，以便将特征集浓缩为负担得起的、准确的分子进展诊断小组。最后，这些资料将在一千组息肉患者中进行验证，以预测临床环境中癌症进展的风险。本应用程序的目标是开发一套可负担得起的、精细的GTM事件集，以回答有关已经开始转变为CRC的息肉中发生的分子事件的基本问题，并与未开始转变为CRC的息肉进行比较。这些研究解决了扩大知识基础的关键需求，在此基础上，医生和患者可以为有结肠直肠息肉转化和进展性恶性肿瘤导致侵袭性、转移性结直肠癌风险的患者做出最佳病例实践决策。

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.