title: MUTYH and the mismatch repair system: partners in crime?
abstract: Biallelic germline mutations of MUTYH-a gene encoding a base excision repair protein-are associated with an increased susceptibility of colorectal cancer. Whether monoallelic MUTYH mutations also increase cancer risk is not yet clear, although there is some evidence suggesting a slight increase of risk. As the MUTYH protein interacts with the mismatch repair (MMR) system, we hypothesised that the combination of a monoallelic MUTYH mutation with an MMR gene mutation increases cancer risk. We therefore investigated the prevalence of monoallelic MUTYH mutations in carriers of a germline MMR mutation: 40 carriers of a truncating mutation (group I) and 36 of a missense mutation (group II). These patients had been diagnosed with either colorectal or endometrial cancer. We compared their MUTYH mutation frequencies with those observed in a group of 134 Dutch colorectal and endometrial cancer patients without an MMR gene mutation (0.7%) and those reported for Caucasian controls (1.5%). In group I one monoallelic MUTYH mutation was found (2.5%). In group II five monoallelic germline MUTYH mutations were found (14%), four of them in MSH6 missense mutation carriers (20%). Of all patients with an MMR gene mutation, only those with a missense mutation showed a significantly higher frequency of (monoallelic) MUTYH mutations than the Dutch cancer patients without MMR gene mutations (P = 0.002) and the published controls (P = 0.001). These results warrant further study to test the hypothesis of mutations in MMR genes (in particular MSH6) and MUTYH acting together to increase cancer risk.
authors.affiliation: Department of Medical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Renée C
authors.initials: RC
authors.lastname: Niessen
authors.forename: Rolf H
authors.initials: RH
authors.lastname: Sijmons
authors.forename: J
authors.initials: J
authors.lastname: Ou
authors.forename: Sandra G M
authors.initials: SG
authors.lastname: Olthof
authors.forename: Jan
authors.initials: J
authors.lastname: Osinga
authors.forename: Marjolijn J
authors.initials: MJ
authors.lastname: Ligtenberg
authors.forename: Frans B L
authors.initials: FB
authors.lastname: Hogervorst
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Weiss
authors.forename: Carli M J
authors.initials: CM
authors.lastname: Tops
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.forename: Geertruida H
authors.initials: GH
authors.lastname: de Bock
authors.forename: Charles H C M
authors.initials: CH
authors.lastname: Buys
authors.forename: Jan H
authors.initials: JH
authors.lastname: Kleibeuker
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins / Q000032:analysis / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000473:pathology; D045647:DNA Glycosylases / Q000235:genetics*; D053843:DNA Mismatch Repair; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics / Q000473:pathology; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D007150:Immunohistochemistry; D053842:Microsatellite Instability; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000032:analysis / Q000235:genetics; D009154:Mutation; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein