title: Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer.
abstract: OBJECTIVE
  Germline mutations in the DNA mismatch repair (MMR) genes MSH2, MSH6, or MLH1 predispose to colorectal cancer (CRC) with an autosomal dominant inheritance pattern. The protein encoded by PMS2 is also essential for MMR; however, alterations in this gene have been documented only in extremely rare cases. We addressed this unexpected finding by analyzing a large series of CRCs.
  
  
  METHODS
  Expression of MSH2, MSH6, MLH1, and PMS2 was studied by immunohistochemistry in 1048 unselected, consecutive CRCs. Where absence of MMR proteins was detected, microsatellite instability and cytosine methylation of the respective gene promoter were analyzed. The DNA of patients presenting with PMS2-deficient cancers was examined for germline and somatic alterations in the PMS2 gene.
  
  
  RESULTS
  An aberrant pattern of MMR protein expression was detected in 13.2% of CRCs. Loss of expression of MSH2, MSH6, or MLH1 was found in 1.4%, 0.5%, and 9.8%, respectively. PMS2 deficiency accompanied by microsatellite instability was found in 16 cases (1.5%) with a weak family history of cancer. The PMS2 promoter was not hypermethylated in these cases. Despite interference of the PMS2 pseudogenes, we identified several heterozygous germline mutations in the PMS2 gene.
  
  
  CONCLUSIONS
  PMS2 defects account for a small but significant proportion of CRCs and for a substantial fraction of tumors with microsatellite instability. However, the penetrance of heterozygous germline mutations in PMS2 is considerably lower than that of mutations in other MMR genes. The possible underlying causes of this unorthodox inheritance pattern are discussed.
authors.affiliation: Institute of Molecular Cancer Research, University of Zurich, Switzerland.
authors.forename: Kaspar
authors.initials: K
authors.lastname: Truninger
authors.forename: Mirco
authors.initials: M
authors.lastname: Menigatti
authors.forename: Judith
authors.initials: J
authors.lastname: Luz
authors.forename: Anna
authors.initials: A
authors.lastname: Russell
authors.forename: Ritva
authors.initials: R
authors.lastname: Haider
authors.forename: Jan-Olaf
authors.initials: JO
authors.lastname: Gebbers
authors.forename: Fridolin
authors.initials: F
authors.lastname: Bannwart
authors.forename: Hueseyin
authors.initials: H
authors.lastname: Yurtsever
authors.forename: Joerg
authors.initials: J
authors.lastname: Neuweiler
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Riehle
authors.forename: Maria Sofia
authors.initials: MS
authors.lastname: Cattaruzza
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
authors.forename: Primo
authors.initials: P
authors.lastname: Schär
authors.forename: Josef
authors.initials: J
authors.lastname: Jiricny
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Marra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D019175:DNA Methylation; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
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; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; C497172:MSH2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes