title: The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations.
abstract: OBJECTIVE
  Although the clinical phenotype of Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers.
  
  
  METHODS
  We performed PMS2 mutation analysis using long-range polymerase chain reaction and multiplex ligation-dependent probe amplification for 99 probands diagnosed with Lynch syndrome-associated tumors showing isolated loss of PMS2 by immunohistochemistry. Penetrance was calculated using a modified segregation analysis adjusting for ascertainment.
  
  
  RESULTS
  Germ-line PMS2 mutations were detected in 62% of probands (n = 55 monoallelic; 6 biallelic). Among families with monoallelic PMS2 mutations, 65.5% met revised Bethesda guidelines. Compared with the general population, in mutation carriers, the incidence of colorectal cancer was 5.2-fold higher, and the incidence of endometrial cancer was 7.5-fold higher. In North America, this translates to a cumulative cancer risk to age 70 years of 15%-20% for colorectal cancer, 15% for endometrial cancer, and 25%-32% for any Lynch syndrome-associated cancer. No elevated risk for non-Lynch syndrome-associated cancers was observed.
  
  
  CONCLUSIONS
  PMS2 mutations contribute significantly to Lynch syndrome, but the penetrance for monoallelic mutation carriers appears to be lower than that for the other mismatch repair genes. Modified counseling and cancer surveillance guidelines for PMS2 mutation carriers are proposed.
authors.affiliation: Human Cancer Genetics Program, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio, USA.
authors.forename: Leigha
authors.initials: L
authors.lastname: Senter
authors.forename: Mark
authors.initials: M
authors.lastname: Clendenning
authors.forename: Kaisa
authors.initials: K
authors.lastname: Sotamaa
authors.forename: Heather
authors.initials: H
authors.lastname: Hampel
authors.forename: Jane
authors.initials: J
authors.lastname: Green
authors.forename: John D
authors.initials: JD
authors.lastname: Potter
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.forename: Kristina
authors.initials: K
authors.lastname: Lagerstedt
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.forename: Joanne
authors.initials: J
authors.lastname: Young
authors.forename: Ingrid
authors.initials: I
authors.lastname: Winship
authors.forename: James G
authors.initials: JG
authors.lastname: Dowty
authors.forename: Darren M
authors.initials: DM
authors.lastname: White
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Laura
authors.initials: L
authors.lastname: Baglietto
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Albert
authors.initials: A
authors.lastname: de la Chapelle
mesh_terms: D000251:Adenosine Triphosphatases / Q000032:analysis / Q000235:genetics*; D000328:Adult; D000368:Aged; D015179:Colorectal Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis / Q000379:methods; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D022521:Ligase Chain Reaction; D008297:Male; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D016017:Odds Ratio; D019683:Penetrance; D010641:Phenotype; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D018570:Risk Assessment
chemical_list: D004268:DNA-Binding Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000251:Adenosine Triphosphatases; C094934:PMS2 protein, human; D000070976:Mismatch Repair Endonuclease PMS2; D045643:DNA Repair Enzymes