title: Two mismatch repair gene mutations found in a colon cancer patient--which one is pathogenic?
abstract: Hereditary nonpolyposis colorectal cancer (HNPCC) is a dominantly inherited cancer syndrome. Germline mutations in five different mismatch repair (MMR) genes, MSH2, MSH6, MLH1, MLH3, and PMS2 are linked to HNPCC. Here, we describe two colon cancer families in which the index patients carry missense mutations in both MSH2 and MSH6. The MSH2 mutation, I145M, is the same in both families, whereas the MSH6 mutations are different (R1095H and L1354Q). The families do not fulfil the international criteria for HNPCC, one family comprising two and the other family four colon cancer patients, all in one generation, resembling a recessive rather than dominant inheritance characteristic of HNPCC. The tumors of the index patients showed microsatellite instability. Functional analysis was performed to determine which one of the mutations could primarily underlie the cancer susceptibility in the families. MSH2 and MSH6 are known to form a heterodimeric complex (MutSalpha) responsible for mismatch recognition. The interaction of each mutated protein with its wild-type partner and with its mutated partner present in the colon cancer patient, and the MMR function of the mutated MutSalpha complexes were determined. Since none of the three mutations affected the MSH2-MSH6 interaction or the function of MutSalpha in an in-vitro MMR assay, our results suggest that alone the mutations do not cause MMR deficiency typical of HNPCC. However, our results do not exclude the possible compound pathogenicity of the two mutations.
authors.affiliation: Department of Biosciences, Division of Genetics, University of Helsinki, Viikinkaari 5, 00014 Helsinki, Finland.
authors.forename: Reetta
authors.initials: R
authors.lastname: Kariola
authors.forename: Robyn
authors.initials: R
authors.lastname: Otway
authors.forename: Karin E
authors.initials: KE
authors.lastname: Lönnqvist
authors.forename: Tiina E
authors.initials: TE
authors.lastname: Raevaara
authors.forename: Finlay
authors.initials: F
authors.lastname: Macrae
authors.forename: Yvonne J
authors.initials: YJ
authors.lastname: Vos
authors.forename: Maija
authors.initials: M
authors.lastname: Kohonen-Corish
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Minna
authors.initials: M
authors.lastname: Nyström-Lahti
mesh_terms: D016367:Baculoviridae / Q000235:genetics; D020137:Base Pair Mismatch; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005816:Genetic Complementation Test; D020022:Genetic Predisposition to Disease; D005822:Genetic Vectors; D005823:Genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D051718:MutS Homolog 2 Protein; D016296:Mutagenesis; D020125:Mutation, Missense; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000473:pathology
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; C497172:MSH2 protein, human; D051718:MutS Homolog 2 Protein