How Do Colorectal Cancers Arise Despite Surveillance?

描述（申请人提供）：人们普遍认为结直肠癌是通过腺瘤-癌序列发展而来的。按照这种模式，所有的癌症都应该通过监测和息肉切除来预防。然而，在大多数监测研究中，一些癌症不可避免地出现在阴性临床检查后几年。目前尚不清楚这种“间断性”癌症是如何出现的，但要么是在上次“阴性”检查中遗漏了腺瘤，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）发生种系突变的高风险个体进行的临床监测项目中，发现了大量这样的间隔期癌症。这些间隔期癌症提供了独特的机会来严格理解为什么预防失败。关键的新兴技术是一种从癌症突变推断时间的新能力。分子肿瘤时钟可以定量地推断MMR丢失后的时间，以及癌症最终扩散的年龄——癌症中突变越多，这些时间间隔就越大。区分监测不足导致的失败（“漏诊腺瘤”）和HNPCC结直肠癌独特的生物学特性导致的失败（“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。

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.