title: Novel findings in Swedish patients with MYH-associated polyposis: mutation detection and clinical characterization.
abstract: OBJECTIVE
  Biallelic mutations in the base-excision repair gene MYH have recently been associated with recessive inheritance of multiple colorectal adenomas. An investigation and characterization of MYH mutations in Swedish patients were therefore carried out.
  
  
  METHODS
  A set of 15 unrelated adenomatous polyposis coli (APC)-mutation negative patients from the Swedish Polyposis Registry was screened for germline mutations in the MYH gene. The patients were clinically characterized and compared with 43 APC-mutation positive probands diagnosed during the same period.
  
  
  RESULTS
  Disease-causing biallelic MYH mutations were identified in 6 patients (40%). The mean age at diagnosis was 47.8 years versus 34.1 years in APC-mutation positive patients (P = .015). Colorectal cancer at diagnosis of polyposis was present in 67% (4/6) of the patients, and all were right-sided, compared with only 19% versus 12.5% right-sided cancer in APC-mutation positive patients. Upper gastrointestinal manifestations were diagnosed in 1 of 5 compared with 23 of 27 in APC-mutation positive patients (odds ratio, 23; 95% confidence interval, 2-263; P = .0086). One family exhibited apparent dominant inheritance of colorectal adenomatous polyposis. Two new pathogenic mutations, MYH p.G175E and p.P391L, were identified. The mutations are argued to introduce profound changes in substrate-recognizing domains of the protein.
  
  
  CONCLUSIONS
  Biallelic MYH mutations, including 2 novel mutations, were found in a substantial number of the patients with multiple colorectal adenomas who were negative for APC-mutation. The examined MYH-mutation positive patients were found to have higher risks of colorectal cancer at diagnosis, right-sided location of cancers, and a significantly lower incidence of upper gastrointestinal manifestations, compared with APC-mutation positive patients.
authors.affiliation: Department of Clinical Genetics, Göteborg University, Sahlgrenska University Hospital/Ostra, Göteborg, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Kanter-Smoler
authors.forename: Jan
authors.initials: J
authors.lastname: Björk
authors.forename: Kaisa
authors.initials: K
authors.lastname: Fritzell
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Engwall
authors.forename: Birgitta
authors.initials: B
authors.lastname: Hallberg
authors.forename: Göran
authors.initials: G
authors.lastname: Karlsson
authors.forename: Henrik
authors.initials: H
authors.lastname: Grönberg
authors.forename: Per
authors.initials: P
authors.lastname: Karlsson
authors.forename: Arne
authors.initials: A
authors.lastname: Wallgren
authors.forename: Jan
authors.initials: J
authors.lastname: Wahlström
authors.forename: Rolf
authors.initials: R
authors.lastname: Hultcrantz
authors.forename: Margareta
authors.initials: M
authors.lastname: Nordling
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000367:Age Factors; D000368:Aged; D045647:DNA Glycosylases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D017491:Genes, APC; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D040582:Inheritance Patterns; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D011379:Prognosis; D013548:Sweden
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase