title: Report of a family segregating mutations in both the APC and MSH2 genes: juvenile onset of colorectal cancer in a double heterozygote.
abstract: OBJECTIVE
  Mutations in DNA mismatch repair genes are associated with high risk of digestive malignancies [hereditary non-polyposis colorectal cancer (HNPCC); Lynch syndrome]; mutations of APC and MYH are associated with classic and attenuated familial adenomatous polyposis (FAP). Although the early onset of tumors in both syndromes is characteristic of their genetic origin, pediatric malignancies remain rare. Certain reports have found familial colorectal cancer (CRC) occurring in very young patients associated with mutations in more than one gene.
  
  
  METHODS
  A family corresponding to the Amsterdam criteria for HNPCC, including two cases of colorectal cancer before the age of 25 years, was analyzed for mutations in the MSH2 genes by sequencing. Because polyposis was observed in a patient who developed CRC at age 16, the APC gene was also sequenced.
  
  
  RESULTS
  A truncating mutation in the MSH2 gene, c.258_259delTG, was carried by patients developing cancer of the colon (two patients), uterus, kidney, bladder, and/or small intestine at ages 16, 24, 43, 44, 45, and 57, respectively. A patient with CRC at age 16 was found to carry the APC c.3183_3187del5 mutation as well as the MSH2 mutation, and it is inferred that her father, deceased of CRC at age 24, was also a double heterozygote.
  
  
  CONCLUSIONS
  These results confirm that vigilance is required when interpreting molecular results for families with very young patients, as more than one gene may contribute to the genetic risk. Cancer screening measures must also be adapted to the earlier and more penetrant risk to double heterozygotes.
authors.affiliation: Laboratoire Diagnostic Génétique et Moléculaire, Centre Jean Perrin, 58 rue Montalembert, 63011 Clermont-Ferrand, France.
authors.forename: N
authors.initials: N
authors.lastname: Uhrhammer
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Bignon
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000483:Alleles; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D005190:Family; D005260:Female; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D004273:DNA, Neoplasm; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein