How Do Colorectal Cancers Arise Despite Surveillance?

描述（由申请人提供）：结肠直肠癌被广泛认为是通过腺瘤-癌症序列发展的。通过这种模式，所有癌症都应该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阴性临床检查后几年才出现。目前尚不清楚这种“间歇性”癌症是如何出现的，但要么是在最后一次“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）发生种系突变的高危个体进行临床监测期间，发现了大量此类间期癌。这些间歇性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中推断时间的新能力。分子肿瘤时钟可以定量地推断自MMR丧失以来的时间，以及最终癌症扩展的年龄-癌症中的突变越多，这些间隔就越大。区分监测不充分（“漏诊腺瘤”）和HNPCC结直肠癌独特生物学（“快速组织学或遗传学进展”）导致的失败，对于开发更有效的预防和治疗结直肠癌策略至关重要。

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.