Colorectal pretumor progression before and after loss of DNA mismatch repair.
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.
Calabrese
Peter
P
Department of Biological Sciences, Program in Molecular and Computational Biology, University of Southern California, Los Angeles, California 90033, USA.
Tsao
Jen-Lan
JL
Yatabe
Yasushi
Y
Salovaara
Reijo
R
Mecklin
Jukka-Pekka
JP
Järvinen
Heikki J
HJ
Aaltonen
Lauri A
LA
Tavaré
Simon
S
Shibata
Darryl
D
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000367:Age Factors; D020137:Base Pair Mismatch / Q000235:genetics; D002352:Carrier Proteins; D002471:Cell Transformation, Neoplastic; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D018450:Disease Progression; D018095:Germ-Line Mutation; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D008954:Models, Biological; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D011230:Precancerous Conditions / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012189:Retrospective Studies; D013997:Time Factors
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein