How Do Colorectal Cancers Arise Despite Surveillance?

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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.