How Do Colorectal Cancers Arise Despite Surveillance?

尽管有监测，结直肠癌是如何发生的？

• 批准号: 6859788
• 负责人: Darryl K Shibata
• 金额: $ 30.91万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6859788
• 关键词: adenomatous polyps; cancer prevention; carcinogenesis; clinical research; colorectal neoplasms; cytogenetics; gene mutation; histopathology; human tissue; neoplasm /cancer diagnosis; neoplasm /cancer genetics; neoplastic growth; preneoplastic state

DESCRIPTION (provided by applicant): Colorectal cancers are widely believed to develop through an adenoma-cancer sequence. By this paradigm, all cancers should be preventable with surveillance and polypectomy. However, in most surveillance studies, some cancers inevitably appear only a few years after negative clinical examinations. It is uncertain how such "interval" cancers appear, but either an adenoma was missed during the last "negative" examination, or there was an unexpected "rapid" mode of progression. A large number of such interval cancers have been found during an ongoing clinical surveillance program of high risk individuals with germline mutations in DNA mismatch repair genes (MMR), or hereditary nonpolyposis colorectal cancer (HNPCC). These interval cancers provide unique opportunities to rigorously understand why prevention fails. The key emerging technology is a new capability that infers time from cancer mutations. A molecular tumor clock can quantitatively infer times since MMR loss, and ages of final cancer expansions---the more mutations in a cancer, the greater these intervals. Distinguishing between failure from inadequate surveillance ("missed adenomas"), and failure due to the unique biology of HNPCC colorectal cancers ("rapid histologic or genetic progression"), is critical for the development of more effective strategies to prevent and treat colorectal cancer.

描述（由申请人提供）：广泛认为结直肠癌是通过腺瘤癌序列发展的。通过这种范式，所有癌症都应通过监测和多型切除术来预防。但是，在大多数监视研究中，有些癌症不可避免地在阴性临床检查后仅几年才出现。不确定这种“间隔”癌症是如何出现的，但是在上次“阴性”检查中错过了腺瘤，或者存在意外的“快速”进展方式。在正在进行的临床监测计划中发现了大量此类间隔癌症，该计划对DNA不匹配修复基因（MMR）或遗传性非杂质病大肠癌（HNPCC）的高风险患者（MMR）中的生殖线突变（HNPCC）。这些间隔癌症提供了独特的机会，以严格了解预防失败的原因。关键的新兴技术是一种新的能力，它会渗透到癌症突变中的时间。分子肿瘤时钟可以自MMR丢失以来定量推断时间，以及最终癌症的扩张年龄 - 癌症中的突变越多，这些间隔就越大。区分失败与HNPCC结直肠癌的独特生物学（“快速的组织学或遗传进展”）引起的失败对于制定更有效的预防和治疗结直肠癌至关重要。