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(American Journal of Pathology. 2004;164:1447-1453.)
© 2004 American Society for Investigative Pathology

Colorectal Pretumor Progression Before and After Loss of DNA Mismatch Repair

Peter Calabrese^*, Jen-Lan Tsao, Yasushi Yatabe, Reijo Salovaara, Jukka-Pekka Mecklin^¶, Heikki J. Järvinen^||, Lauri A. Aaltonen, Simon Tavaré^* and Darryl Shibata

From the Department of Biological Sciences,^* Program in Molecular and Computational Biology, University of Southern California, Los Angeles, California; the Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, California; the Departments of Pathology and Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland; the Second Department of Surgery,^¶ Helsinki University Central Hospital, Helsinki, Finland; and Jyvaskyla Central Hospital,|| Jyvaskyla, Finland

A pretumor progression model predicts many oncogenic cancer mutations may first accumulate in normal appearing colon. Although direct observations of early pretumor mutations are impractical, it may be possible to retrospectively reconstruct tumor histories from contemporary cancer mutations. To infer when and in what order mutations occur during occult pretumor progression, we examined 14 cancers from individuals with heterozygous germline mutations in DNA mismatch repair (MMR) genes or hereditary nonpolyposis colorectal cancer (HNPCC). Somatic inactivation of the normal allele occurs sometime during a lifetime and results in loss of MMR, elevated mutation rates, and subsequent widespread somatic microsatellite mutations in HNPCC cancers. Patient ages at MMR loss can be estimated because intervals between MMR loss and cancer removal can be inferred from numbers of microsatellite tumor mutations. The relative order of MMR loss during pretumor progression may also be inferred from its collective ages of occurrence. Somatic MMR loss preceded cancer removal by an average of 6.1 years, occurred relatively late in life (average of 41.6 versus 47.7 years at cancer removal), and was a surprisingly late (fifth or sixth) step. Calculations indicate five or six oncogenic mutations could accumulate with relatively normal replication fidelity in normal appearing colon. HNPCC pretumor progression essentially begins from birth and ends with MMR loss, implying elevated mutation rates and tumorigenesis may be unnecessary for most progression.

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