title: The colon cancer burden of genetically defined hereditary nonpolyposis colon cancer.
abstract: OBJECTIVE
  Estimates of the frequency of hereditary nonpolyposis colon cancer (HNPCC) based on clinical criteria have varied widely. Recent studies of germline mismatch repair gene mutations have suggested that HNPCC accounts for close to 3% of all colon cancer, but this estimate may have been inflated by inclusion of founder effects peculiar to Finland. We therefore determined by genetic criteria the colon cancer burden associated with HNPCC in a population-based study of 1066 individuals from Utah and California.
  
  
  METHODS
  The coding regions of mismatch repair genes hMSH2 and hMLH1 were sequenced from the germline of those individuals whose tumors exhibited microsatellite instability.
  
  
  RESULTS
  Microsatellite instability was present in 16% (171/1066) of tumors. Pathogenic germline mismatch repair gene mutations were identified in 7 individuals, and missense amino acid changes of uncertain significance were identified in another 6 individuals. After adjusting for the availability of sufficient germline DNA for sequencing, the 7 clearly pathogenic mutations accounted for 0.86% of colon cancer at the population level. Individuals with these mutations were significantly younger, more likely to have a family history of colon and endometrial cancer, and more likely to have first-degree relatives with a young-age onset of colon cancer than individuals with unstable tumors but without germline mutations (P < 0.01).
  
  
  CONCLUSIONS
  We conclude that genetically defined HNPCC accounts for a very small percentage of colon cancer at the population level, a percentage less than that estimated by most previous clinical studies.
authors.affiliation: Department of Pathology, University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA. wsamowitz@msscc.med.utah.edu
authors.forename: W S
authors.initials: WS
authors.lastname: Samowitz
authors.forename: K
authors.initials: K
authors.lastname: Curtin
authors.forename: H H
authors.initials: HH
authors.lastname: Lin
authors.forename: M A
authors.initials: MA
authors.lastname: Robertson
authors.forename: D
authors.initials: D
authors.lastname: Schaffer
authors.forename: M
authors.initials: M
authors.lastname: Nichols
authors.forename: K
authors.initials: K
authors.lastname: Gruenthal
authors.forename: M F
authors.initials: MF
authors.lastname: Leppert
authors.forename: M L
authors.initials: ML
authors.lastname: Slattery
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D020137:Base Pair Mismatch; D002140:California / Q000453:epidemiology; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology* / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005091:Exons; D005190:Family; D005260:Female; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics; D013548:Sweden / Q000453:epidemiology; D014589:Utah / Q000453:epidemiology
chemical_list: 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