title: Analysis of MUTYH genotypes and colorectal phenotypes in patients With MUTYH-associated polyposis.
abstract: OBJECTIVE
  Biallelic mutations in the base excision DNA repair gene MUTYH lead to MUTYH-associated polyposis (MAP) and predisposition to colorectal cancer (CRC). Functional studies have demonstrated significant differences in base recognition and glycosylase activity between various MUTYH mutations, notably for the 2 mutations most frequently reported in MAP patients: Y179C and G396D (previously annotated as Y165C and G382D). Our goal was to establish correlations between genotypes and colorectal phenotype of patients with MAP.
  
  
  METHODS
  In this multicenter study, we analyzed genotype and phenotype data from 257 MAP patients. Data included age at presentation of MAP, polyp count, and the occurrence, location, and age at presentation of CRC.
  
  
  RESULTS
  Patients with a homozygous G396D mutation or compound heterozygous G396D/Y179C mutations presented later with MAP and had a significantly lower hazard of developing CRC than patients with a homozygous Y179C mutation (P < .001). The mean ages of CRC diagnosis in patients were 58 years (homozygous G396D) and 52 years (compound heterozygous G396D/Y179C) versus 46 years (homozygous Y179C; P = .001, linear regression).
  
  
  CONCLUSIONS
  Our study identified the phenotypic effects of Y179C as relatively severe and of G396D as relatively mild. These clinical data are in accord with findings from in vitro functional assays. Genotypic stratification may become useful in the development of guidelines for counseling, surveillance, and management of families with MAP.
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. m.nielsen@lumc.nl
authors.forename: Maartje
authors.initials: M
authors.lastname: Nielsen
authors.forename: Mirjam C
authors.initials: MC
authors.lastname: Joerink-van de Beld
authors.forename: Natalie
authors.initials: N
authors.lastname: Jones
authors.forename: Stefanie
authors.initials: S
authors.lastname: Vogt
authors.forename: Carli M
authors.initials: CM
authors.lastname: Tops
authors.forename: Hans F A
authors.initials: HF
authors.lastname: Vasen
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D015331:Cohort Studies; D003106:Colon / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology; D045647:DNA Glycosylases / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D044483:Intestinal Polyposis / Q000235:genetics* / Q000473:pathology*; D016014:Linear Models; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012007:Rectum / Q000473:pathology*; D055815:Young Adult
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase