title: Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair.
abstract: OBJECTIVE
  We ascertained a large kindred with an excess of Lynch syndrome-associated cancers. Our objective was to determine if a defect in one of the DNA mismatch repair (DMMR) genes was the probable cause of cancer susceptibility as microsatellite instability (MSI) and immunohistochemical (IHC) analysis of the probands' tumors did not provide a clear indication.
  
  
  METHODS
  A detailed history and review of medical records was undertaken to construct a four-generation pedigree. Blood samples were obtained for analysis of germline DNA. Polymorphic repeats from the MLH1, MSH2, MSH6, and PMS2 loci were genotyped and the co-segregation of markers and disease was assessed. DMMR gene expression for all available tumors was evaluated by IHC. Combined bisulfite restriction analysis (COBRA) of MLH1 was utilized to test for germline epimutation.
  
  
  RESULTS
  Four gynecologic carcinomas, 3 colon carcinomas, and 13 cases of adenomatous polyps were identified. The family met Amsterdam II criteria. The mean age of cancer diagnosis in the kindred was 63 years (range 44-82 years). DNA marker analyses excluded linkage to MLH1, MSH2, MSH6, and PMS2. Furthermore, MSI and IHC analysis of tumors did not suggest a role for DMMR. Methylation of the MLH1 promoter was identified in the peripheral blood leukocytes (PBLs) of a family member with an early onset colon cancer.
  
  
  CONCLUSIONS
  We identified a large family with multiple Lynch malignancies and no evidence for an inherited defect in DMMR. This family represents an important but poorly understood form of autosomal dominant inherited cancer susceptibility. Aberrant MLH1 promoter methylation in normal tissues may be a marker for cancer susceptibility in families such as this.
authors.affiliation: Divison of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, 4911 Barnes-Jewish Hospital Plaza, 3rd Floor Maternity, St. Louis, MO 63110, USA. casea@wudosis.wustl.edu
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Case
authors.forename: Israel
authors.initials: I
authors.lastname: Zighelboim
authors.forename: David G
authors.initials: DG
authors.lastname: Mutch
authors.forename: Sheri A
authors.initials: SA
authors.lastname: Babb
authors.forename: Amy P
authors.initials: AP
authors.lastname: Schmidt
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Whelan
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000235:genetics; D000251:Adenosine Triphosphatases / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016000:Cluster Analysis; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000096:biosynthesis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070976:Mismatch Repair Endonuclease PMS2; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000096:biosynthesis / Q000235:genetics; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D010375:Pedigree; D011401:Promoter Regions, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear 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