Two mismatch repair gene mutations found in a colon cancer patient--which one is pathogenic?
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.
Kariola
Reetta
R
Department of Biosciences, Division of Genetics, University of Helsinki, Viikinkaari 5, 00014 Helsinki, Finland.
Otway
Robyn
R
Lönnqvist
Karin E
KE
Raevaara
Tiina E
TE
Macrae
Finlay
F
Vos
Yvonne J
YJ
Kohonen-Corish
Maija
M
Hofstra
Robert M W
RM
Nyström-Lahti
Minna
M
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
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