title: Little evidence for involvement of MLH3 in colorectal cancer predisposition.
abstract: Mutations in the DNA MMR genes MSH2, MLH1, MSH6 and PMS2 underlie a large subset of HNPCC cases, and a hallmark of the tumors is MSI. In many HNPCC families, however, a causative mutation has not been found. Therefore, the involvement of additional, thus far unknown, genes in MSI as well as MSS colorectal tumor predisposition is possible. The role of a relatively recently cloned MMR gene, MLH3, in familial CRC has been studied; but the results appear somewhat conflicting. To further evaluate the role of MLH3 in CRC predisposition, we analyzed 30 Finnish CRC cases for germline mutations by sequencing. These cases were selected from a large series of Finnish CRC patients, to match features previously proposed to associate with MLH3 germline defects. We found 5 missense variants, 4 of which were also found in Finnish cancer-free controls. The only remaining variant does not appear to be an attractive candidate for a disease-associated mutation because the amino acid change is located outside the conserved residues. We also screened for the previously reported variants, including a frameshift change, the most likely pathogenic MLH3 mutation observed so far. The frameshift was not present in the 30 CRC cases or in 700 cancer-free controls. While it is a difficult task to exclude a role of MLH3 in HNPCC, our study could not confirm a role for MLH3 in CRC predisposition.
authors.affiliation: Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Tuija
authors.initials: T
authors.lastname: Hienonen
authors.forename: Päivi
authors.initials: P
authors.lastname: Laiho
authors.forename: Reijo
authors.initials: R
authors.lastname: Salovaara
authors.forename: Jukka-Pekka
authors.initials: JP
authors.lastname: Mecklin
authors.forename: Heikki
authors.initials: H
authors.lastname: Järvinen
authors.forename: Pertti
authors.initials: P
authors.lastname: Sistonen
authors.forename: Päivi
authors.initials: P
authors.lastname: Peltomäki
authors.forename: Rainer
authors.initials: R
authors.lastname: Lehtonen
authors.forename: Nina N
authors.initials: NN
authors.lastname: Nupponen
authors.forename: Virpi
authors.initials: V
authors.lastname: Launonen
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004260:DNA Repair / Q000235:genetics*; D004273:DNA, Neoplasm / Q000032:analysis; D005387:Finland; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D000070956:MutL Proteins; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D004273:DNA, Neoplasm; C403623:MLH3 protein, human; D000070956:MutL Proteins