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

描述(申请人提供)：结肠镜检查是识别和去除结直肠癌(CRC)前驱病变的有效干预措施。自从结肠镜筛查使医生能够发现和切除息肉(CRC的前驱病变)以来，20年来，美国CRC的发病率下降了30%。虽然结肠镜检查可以让医生观察息肉的内窥镜表现，并由病理学家进行组织学评估，但这些诊断性仔细检查的措施无法确定息肉属性，从而预测哪些病变最有可能通过导致息肉进展为癌症的分子事件过渡。虽然大多数结直肠癌是由腺瘤性息肉恶变引起的，但只有5%的息肉进展为癌症。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。作为对挑衅性问题14的回答，我们试图通过比较患有癌症的息肉和没有癌症的息肉来确定结直肠癌的可定义特性。由于在分子水平上没有更好地了解息肉进展为癌症的生物学基础，医生和患者在对预测息肉转化为癌症的风险的因素缺乏完整信息的情况下就决定治疗方案。这些研究建议确定息肉的分子特征，以区分给定病变的临床行为，以便根据患者息肉进展为癌症的可能性确定个别患者的最佳治疗机会。最近利用基因组、mRNA和微小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的息肉和癌症来描述癌症发生的分子特征。这项研究的第一个目的是比较在癌旁息肉患者和无癌息肉患者的息肉组织中发现的分子变化，这些息肉在大小、组织学和不典型增生程度上相似。第二个目标将通过测试100组息肉的精细轮廓来完善在Aim One中发现的分子特征的轮廓，以便将轮廓集浓缩成负担得起的、准确的分子进程诊断面板。最后，这些特征将在1000组患者息肉中得到验证，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套负担得起的、精致的GTM事件，以回答有关息肉中发生的分子事件的基本问题，这些事件发生在已经开始转化为结直肠癌的息肉中，而不是那些没有转化的息肉中。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大肠息肉转化和导致侵袭性、转移性结直肠癌的进行性恶性肿瘤的风险患者做出最佳病例实践决定。 与公共卫生相关：在美国，结直肠癌的发病率有所下降，因为结肠镜检查可以早期发现并切除息肉，息肉是先兆病变，可以阻止癌症的发展，但尽管如此，结直肠癌仍然是美国癌症死亡的第二大原因。接受结肠镜检查的人中有三分之一会有腺瘤性息肉，但这些息肉发展成癌症的可能性不到5%。为什么一个息肉会发展成癌症，而另一个不会？在这项应用中，我们将确定哪些基因、mRNA表达和基因甲基化模式将区分已经转化为癌症的息肉和没有转化为癌症的息肉。

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.