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 ins tability (MI+; replication error) phenotype in certain human cancers. We previously reported that;MIC tumor-specific repeat number alteratio n at 13 consecutive trinucleotide (CAG) repeats within a coding exon o f 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 ca ncers 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 wi thin the seventh exon of the hMSH3 gene, a known mismatch repair gene that is responsible for repair of mismatch loops of two to four nucleo tides. However, neither of these mutations was detected in 15 tumors w ith a lower incidence of MI+ loci, Similar repeat number alterations w ere less frequent in CAG repeats from other genes in all of the MI+ tu mors we examined. These results indicate the presence of a novel casca de of mutational events that may be involved in acquisition of the mal ignant phenotype of human colorectal cancers with genetic instability.