title: Contribution of common monoallelic MUTYH gene variants in German patients with familial colorectal cancer.
abstract: Mutations of the base excision repair gene MUTYH have been reported as underlying genetic defects in autosomal-recessive familial adenomatous polyposis (FAP). Our aim was to determine the frequency of the most common mutations (p.Tyr165Cys and p.Gly382Asp) in patients with strong evidence for familial colorectal cancer (fCRC).
  
  
  METHODS
  We recruited 93 patients with fCRC but no indication for monogenic CRC syndromes (FAP, hereditary non-polyposis colorectal cancer). Tumors showed regular expression of MLH1 and MSH2, and microsatellite instability was excluded. Sporadic CRC patients (n=93) and 'hyper-normal' controls without any adenomas in screening colonoscopies (n=93) were studied for comparison.
  
  
  RESULTS
  In the fCRC group, two patients carried biallelic mutations (p.Tyr165Cys/p.Tyr165Cys, p.Tyr165Cys/p.Gly382Asp), while four patients displayed a heterozygous genotype (3 x p.Tyr165Cys/wt, 1 x p.Gly382Asp/wt). In contrast, only two p.Gly382Asp/wt patients were detected in the sporadic CRC group and one p.Gly382Asp carrier was observed in 'hyper-normal' controls, and the p.Tyr165Cys risk allele was absent in both control groups. Association tests demonstrated an increased odds ratio (OR) for CRC in carriers of the p.Tyr165Cys risk allele among fCRC patients, as compared to sporadic CRC patients and controls (OR 2.38; p=0.03).
  
  
  CONCLUSIONS
  In our cohort the prevalence of pathogenic MUTYH mutations was increased among fCRC patients compared to sporadic CRC and controls. The association of the p.Tyr165Cys mutation with fCRC indicates that this variant represents a susceptibility factor in a defined subgroup of CRC patients with a positive family history.
authors.affiliation: Department of Internal Medicine I, University Hospital Bonn, University of Bonn, Bonn, Germany. frank.gruenhage@ukb.uni-bonn.de
authors.forename: Frank
authors.initials: F
authors.lastname: Grünhage
authors.forename: Matthias
authors.initials: M
authors.lastname: Jungck
authors.forename: Christof
authors.initials: C
authors.lastname: Lamberti
authors.forename: Hildegard
authors.initials: H
authors.lastname: Schulte-Witte
authors.forename: Dominik
authors.initials: D
authors.lastname: Plassmann
authors.forename: Ursula
authors.initials: U
authors.lastname: Becker
authors.forename: Nils
authors.initials: N
authors.lastname: Rahner
authors.forename: Stefan
authors.initials: S
authors.lastname: Aretz
authors.forename: Nicolaus
authors.initials: N
authors.lastname: Friedrichs
authors.forename: Reinhard
authors.initials: R
authors.lastname: Buettner
authors.forename: Tilman
authors.initials: T
authors.lastname: Sauerbruch
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
mesh_terms: D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics*; D045647:DNA Glycosylases / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005858:Germany; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction
chemical_list: D045647:DNA Glycosylases; C061738:mutY adenine glycosylase