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

时间流逝到癌症：定义从息肉到结直肠癌的转变（PQ14）

• 批准号: 8383183
• 负责人: LISA Allyn BOARDMAN
• 金额: $ 65.41万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-18 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8383183
• 关键词: Accounting; Address; Adenomatous Polyps; Adoption; Alcohol consumption; Appearance; Base Pairing; Behavior; Benign; Biological; Biological Markers; Cancer Etiology; Cessation of life; Characteristics; Chromosomal Instability; Clinic; Clinical; Colon; Colonoscopy; Colorectal; Colorectal Cancer; Colorectal Polyp; Commit; Copy Number Polymorphism; CpG Islands; Data; Detection; Diagnostic; Dietary Factors; Disease; Dysplasia; Early Diagnosis; Epidemiologic Factors; Epigenetic Process; Epithelium; Evaluation; Event; Excision; Exhibits; Family history of; Formalin; Freezing; Future; Gene Expression Profile; Genes; Genetic; Genome; Genomics; Genotype; Goals; Health; Histologic; Histology; Incidence; Individual; Institutional Review Boards; Intervention; Lesion; Malignant - descriptor; Malignant Neoplasms; Measures; Messenger RNA; Methylation; MicroRNAs; Microsatellite Repeats; Molecular; Molecular Analysis; Molecular Profiling; Non-Malignant; Paraffin Embedding; Pathologist; Pathway interactions; Patient Care; Patients; Pattern; Phenotype; Physicians; Polyps; Probability; Property; Protocols documentation; Publishing; Recommendation; Recurrence; Research; Resolution; Resources; Risk; Screening procedure; Testing; The Cancer Genome Atlas; Time; Tissue Sample; Tissues; Tobacco use; United States; base; biobank; cancer genome; cancer risk; carcinogenesis; design; effective intervention; falls; follow-up; gastrointestinal; high risk; knowledge base; mRNA Expression; metastatic colorectal; response; tumor progression; uptake

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.

描述（由申请人提供）：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。自从采用结肠镜检查以来，医生能够发现并切除息肉（结直肠癌的前兆病变），二十年来，结直肠癌的发病率在美国下降了 30%。虽然结肠镜检查允许医生观察息肉的内窥镜外观并由病理学家进行组织学评估，但这些诊断检查措施无法定义息肉的特性，无法预测哪些病变最有可能通过分子事件转变，从而使息肉发展为癌症。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，最佳实践方案无法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有癌症的息肉来确定 CRC 的可定义特性。如果不能在分子水平上更好地了解息肉进展为癌症的生物学基础，医生和患者就无法获得有关预测息肉转变为癌症风险的因素的完整信息，从而做出治疗方案的决定。 这些研究旨在确定息肉的分子特征，以区分特定病变的临床行为，以便根据息肉进展为癌症的可能性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 转录组或甲基化组 (GTM) 的分子分析，试图通过研究不同个体的独立息肉和癌症来描述癌发生的分子特征。这项研究的第一个目的是比较癌症邻近息肉个体患者与无癌息肉患者的息肉组织中发现的分子变化，这些患者在大小、组织学和不典型增生程度方面相似。第二个目标将通过在一百组息肉上测试这些精细的特征来完善目标一中发现的分子特征的概况，以便将概况集浓缩为负担得起的、准确的分子进展诊断组。最后，这些资料将在一千组息肉患者中得到验证，以预测临床环境中的癌症进展风险。 该应用的目标是开发一套负担得起的、精致的 GTM 事件，回答有关已开始转化为 CRC 的息肉与尚未转化为 CRC 的息肉中发生的分子事件的基本问题。这些研究满足了扩大知识基础的迫切需求，医生和患者可以根据这些知识为面临结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案例实践决策。 公共卫生相关性：在美国，随着结肠镜检查的普及，早期发现和切除息肉（前体病变）可以阻止癌症的发展，但尽管如此，结直肠癌仍然是癌症死亡的第二大原因在美国。三分之一接受结肠镜检查的人会患有腺瘤性息肉，但这些息肉发展为癌症的几率不到 5%。为什么一个息肉会发展成癌症，而另一个却不会？在此应用中，我们将确定哪些基因、mRNA 表达和基因甲基化模式可以区分已经转化为癌症的息肉和尚未转化为癌症的息肉。