Close correlation between mutations of E2F4 and hMSH3 genes in colorectal cancers with microsatellite instability.
Defects in mismatch repair function can lead to the microsatellite instability (MI+; replication error) phenotype in certain human cancers. We previously reported that MI+ tumor-specific repeat number alteration at 13 consecutive trinucleotide (CAG) repeats within a coding exon of the E2F4 gene is a possible target of the defective repair pathway. Additional investigations revealed that E2F4 mutations are common (11 of 17 cases, 65%, mostly deletions) in a subset of human colorectal cancers with extensive MI+ phenotype, with respect to the proportion of loci affected and that most of these E2F4-mutated tumors (9 of 11, 82%) were accompanied by frameshift mutations in a polyadenine stretch within the seventh exon of the hMSH3 gene, a known mismatch repair gene that is responsible for repair of mismatch loops of two to four nucleotides. However, neither of these mutations was detected in 15 tumors with a lower incidence of MI+ loci. Similar repeat number alterations were less frequent in CAG repeats from other genes in all of the MI+ tumors we examined. These results indicate the presence of a novel cascade of mutational events that may be involved in acquisition of the malignant phenotype of human colorectal cancers with genetic instability.
Ikeda
M
M
First Department of Surgery, Okayama University Medical School, Japan.
Orimo
H
H
Moriyama
H
H
Nakajima
E
E
Matsubara
N
N
Mibu
R
R
Tanaka
N
N
Shimada
T
T
Kimura
A
A
Shimizu
K
K
D015179:Colorectal Neoplasms / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D016368:Frameshift Mutation; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D014157:Transcription Factors