MUTYH and the mismatch repair system: partners in crime?
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.
Niessen
Renée C
RC
Department of Medical Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Sijmons
Rolf H
RH
Ou
J
J
Olthof
Sandra G M
SG
Osinga
Jan
J
Ligtenberg
Marjolijn J
MJ
Hogervorst
Frans B L
FB
Weiss
Marjan M
MM
Tops
Carli M J
CM
Hes
Frederik J
FJ
de Bock
Geertruida H
GH
Buys
Charles H C M
CH
Kleibeuker
Jan H
JH
Hofstra
Robert M W
RM
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
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