title: Lynch syndrome-associated extracolonic tumors are rare in two extended families with the same EPCAM deletion.
abstract: OBJECTIVE
  The Lynch syndrome (LS) is an inherited cancer syndrome showing a preponderance of colorectal cancer (CRC) in context with endometrial cancer and several other extracolonic cancers, which is due to pathogenic mutations in the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2. Some families were found to show a LS phenotype without an identified MMR mutation, although there was microsatellite instability and absence of MSH2 expression by immunohistochemistry. Studies of a subset of these families found a deletion at the 3' end of the epithelial cell adhesion molecule (EPCAM) gene, causing transcription read-through resulting in silencing of MSH2 through hypermethylation of its promoter. The tumor spectrum of such families appears to differ from classical LS.
  
  
  METHODS
  Our study of two large families (USA Family R and Dutch Family A) with an EPCAM deletion was carried out using each institution's standard family study protocol. DNA was extracted from peripheral blood and EPCAM deletion analysis was performed.
  
  
  RESULTS
  Both families were found to harbor the same deletion at the 3' end of EPCAM. Analysis showed that the deletion originated from a common ancestor. Family R and Family A members showed segregation of CRC with the presence of this EPCAM mutation. Compared with classic LS, there were almost no extracolonic cancers.
  
  
  CONCLUSIONS
  Members of Family R and Family A, all with the same EPCAM deletion, predominantly presented with CRC but no LS-associated endometrial cancer, confirming findings seen in other, smaller, LS families with EPCAM mutations. In these EPCAM mutation carriers, cancer surveillance should be focused on CRC.
authors.affiliation: Department of Preventive Medicine, Creighton University, Omaha, Nebraska 68178, USA. htlynch@creighton.edu
authors.forename: Henry T
authors.initials: HT
authors.lastname: Lynch
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Riegert-Johnson
authors.forename: Carrie
authors.initials: C
authors.lastname: Snyder
authors.forename: Jane F
authors.initials: JF
authors.lastname: Lynch
authors.forename: Jill
authors.initials: J
authors.lastname: Hagenkord
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rhees
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Boardman
authors.forename: Janine
authors.initials: J
authors.lastname: Davies
authors.forename: Roland P
authors.initials: RP
authors.lastname: Kuiper
authors.forename: Nicoline
authors.initials: N
authors.lastname: Hoogerbrugge
authors.forename: Marjolijn J L
authors.initials: MJ
authors.lastname: Ligtenberg
mesh_terms: D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000150:complications* / Q000208:ethnology / Q000235:genetics*; D019175:DNA Methylation; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D017353:Gene Deletion; D020868:Gene Silencing; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009426:Netherlands; D010375:Pedigree; D011401:Promoter Regions, Genetic; D014481:United States
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein