Frequent somatic mutations of hMSH3 with reference to microsatellite instability in hereditary nonpolyposis colorectal cancers.
hMSH3 is one of the human DNA mismatch repair genes but has not yet been reported to be associated with hereditary nonpolyposis colorectal cancer. Recently, somatic mutation at a polyadenine tract, i.e., (A)8, in hMSH3 was reported in cancers with microsatellite instability (MI). To clarify the tumorigenetic role of hMSH3, we screened for somatic mutations at the hMSH3 (A)8 repeat in 29 tumors from 23 hereditary nonpolyposis colorectal cancer patients. One or two A deletions in the (A)8 repeat were found in 11 (57.9%) of the 19 MI-positive tumors but not in 10 MI-negative ones, indicating secondary mutations after germline mutations of other mismatch repair genes. Moreover, the MI frequency of three or more nucleotide repeats was higher in hMSH3 (A)8-mutated tumor cells than in nonmutated ones (p<0.05). These data suggest that a mutation of a mismatch repair gene enhances the frequency of another mismatch repair gene mutation, such as of hMSH3, resulting in severe MI.
Akiyama
Y
Y
Department of Hygiene and Oncology, Tokyo Medical and Dental University School of Medicine, Bunkyo-ku, Japan.
Tsubouchi
N
N
Yuasa
Y
Y
D000328:Adult; D001483:Base Sequence; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D005656:Fungal Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D016296:Mutagenesis; D017354:Point Mutation; D018807:Polymorphism, Single-Stranded Conformational; D029701:Saccharomyces cerevisiae Proteins
D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D000074081:MutS Homolog 3 Protein; D029701:Saccharomyces cerevisiae Proteins; C094443:G-T mismatch-binding protein; C078444:MSH3 protein, human; C098790:MSH6 protein, S cerevisiae; C421109:multidrug resistance-associated protein 1