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(申请人提供)：结直肠癌被广泛认为是通过腺瘤-癌症序列发展而来的。根据这一模式，所有癌症都应该可以通过监测和息肉切除术来预防。然而，在大多数监测研究中，一些癌症不可避免地在临床检查阴性后几年才出现。目前还不确定这种“间歇性”癌症是如何出现的，但要么是在上次“阴性”检查中漏掉了一个腺瘤，要么是出现了意想不到的“快速”进展模式。在对DNA错配修复基因(MMR)或遗传性非息肉病性结直肠癌(HNPCC)胚系突变的高危个体进行的临床监测计划中，发现了大量这样的间歇性癌症。这些间歇性癌症为严格理解预防失败的原因提供了独特的机会。关键的新兴技术是一种从癌症突变中推断时间的新能力。分子肿瘤时钟可以定量地推断MMR缺失的时间和癌症最终扩展的年龄-癌症中突变越多，这些间隔就越长。区分失败与不充分的监测(“漏诊的腺瘤”)，以及由于HNPCC结直肠癌独特的生物学特性而导致的失败(“快速的组织学或遗传进展”)，对于制定更有效的预防和治疗结直肠癌的策略至关重要。