title: Germline characterization of early-aged onset of hereditary non-polyposis colorectal cancer.
abstract: OBJECTIVE
  Hereditary non-polyposis colorectal cancer (HNPCC) is characterized by the early onset of colorectal cancer (approximately 40 years). Adolescent colorectal cancer is unusual in HNPCC families. We speculated that some DNA mismatch repair germline mutations might be associated with early onset of disease.
  
  
  METHODS
  Genomic DNA was extracted from members of a kindred with virulent HNPCC fitting the Amsterdam Criteria for HNPCC and sequenced for 2 DNA mismatch repair genes, hMSH2 and hMLH1. A sigmoid adenocarcinoma from the 14-year-old proband was analyzed for highfrequency microsatellite instability and immunostained for DNA mismatch repair gene expression.
  
  
  RESULTS
  A germline mutation was identified at nucleotide 676 (codon 226) of the hMLH1 gene. The C to T transition created a nonsense mutation, truncating the hMLH1 protein. This mutation also alters the splice donor sequence, because nucleotide 676 is 2 base pairs from the 3' end of the exon 8. The proband's tumor demonstrated high-frequency microsatellite instability and displayed loss of hMLH1 expression, indicating bi-allelic inactivation of hMLH1.
  
  
  CONCLUSIONS
  A complex mutation of hMLH1 at codon 226 is associated with adolescent onset of colorectal cancer in an HNPCC family. Genetic screening of other suspected HNPCC families with unusually young members with cancer might reveal certain genotypes with particularly virulent forms of this disease.
authors.affiliation: Division of Gastroenterology and Nutrition, Department of Pediatrics, University of California, San Diego, California, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Huang
authors.forename: J E
authors.initials: JE
authors.lastname: Lavine
authors.forename: P S
authors.initials: PS
authors.lastname: Boland
authors.forename: R O
authors.initials: RO
authors.lastname: Newbury
authors.forename: R
authors.initials: R
authors.lastname: Kolodner
authors.forename: T T
authors.initials: TT
authors.lastname: Pham
authors.forename: C N
authors.initials: CN
authors.lastname: Arnold
authors.forename: C R
authors.initials: CR
authors.lastname: Boland
authors.forename: J M
authors.initials: JM
authors.lastname: Carethers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D017668:Age of Onset; D020137:Base Pair Mismatch; D001706:Biopsy; D002352:Carrier Proteins; D012809:Colon, Sigmoid / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004260:DNA Repair; D005260:Female; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000378:metabolism; D009687:Nuclear Proteins; D010375:Pedigree; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1