Affiliations: University of Southern California, Los Angeles, CA, USA | Gastrointestinal & Other Cancers Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, 6130 Executive Blvd, Rockville, MD 20852, USA
Correspondence:
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Corresponding author: University of Southern California, Keck School of Medicine, 1200 N. State Street, Unit I Room 2428, Los Angeles, CA 90033, USA. Tel.: +1 323 226 7067; Fax: +1 323 226 2686; E-mail: dshibata@hsc.usc.edu.
Abstract: Inactivation of DNA mismatch repair (MMR) is the hallmark of hereditary nonpolyposis colorectal cancer (HNPCC) and sporadic colorectal cancers with microsatellite instability (MSI+). MMR loss results in a markedly elevated mutation rate, and many MS mutations are found in MSI+ cancers. In theory, it is possible to estimate the interval between MMR loss and cancer removal by counting numbers of cancer MS mutations – the more MS mutations, the longer the intervals since MMR loss. Using this somatic molecular clock approach, MMR loss is estimated to precede transformation (clonal expansion) and likely occurs in normal appearing colon. Surprising, ages at MMR loss are more consistent with MMR loss as a relatively late event during progression to MSI+ cancer.
