title: MUTYH hotspot mutations in unselected colonoscopy patients.
abstract: OBJECTIVE
  Biallelic MutY human homologue (MUTYH) germline mutations predispose to recessively inherited adenomatous polyposis, designated MUTYH-associated polyposis (MAP), and colorectal cancer (CRC). The hotspot mutations p.Y179C and p.G396D account for the majority of pathogenic variants of MUTYH in Caucasians. Our aim was to evaluate the prevalence of MUTYH mutations in a prospective cohort of unselected patients with different colorectal diseases.
  
  
  METHODS
  The hotspot mutations p.Y179C and p.G396D were genotyped in 352 consecutive patients undergoing colonoscopy at our tertiary referral centre. Exons 2-14 were sequenced in hotspot mutation carriers to exclude additional variants.
  
  
  RESULTS
  Overall, we identified five heterozygous p.Y179C mutations and three heterozygous p.G396D mutations in seven hotspot mutation carriers (risk allele frequencies 0.7% and 0.4%, respectively). Two of these hotspot mutation carriers harboured a heterozygous p.Q338H variant, which is of uncertain clinical significance, on the other allele. Three individuals were biallelic MUTYH variant carriers (p.Y179C/p.G382D: typical MAP; p.Y179C/p.Q338H: atypical MAP with late onset and lower polyp burden; p.G382D/p.Q338H: inflammatory bowel disease), and four subjects were monoallelic mutation carriers.
  
  
  CONCLUSIONS
  MUTYH-associated disease, and hence genetic counselling and MUTYH genetic testing, should be considered in the clinical routine of an endoscopy unit, but the wide range of phenotypes represents a challenge for patient identification. The clinical significance of p.Q338H should be evaluated in future case-control studies because compound heterozygotes for pathogenic mutations and p.Q338H may be at increased risk for mild polyposis or CRC. In addition, MUTYH should be assessed as a potential susceptibility gene for the development of colitis-associated CRC in future.
authors.affiliation: Department of Medicine II, Saarland University Medical Centre, Homburg, Germany. markus.casper@uks.eu
authors.forename: M
authors.initials: M
authors.lastname: Casper
authors.forename: G
authors.initials: G
authors.lastname: Plotz
authors.forename: B
authors.initials: B
authors.lastname: Juengling
authors.forename: S
authors.initials: S
authors.lastname: Zeuzem
authors.forename: F
authors.initials: F
authors.lastname: Lammert
authors.forename: J
authors.initials: J
authors.lastname: Raedle
mesh_terms: D000236:Adenoma / Q000235:genetics*; D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002277:Carcinoma / Q000235:genetics*; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D006580:Genetic Carrier Screening; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase