Genetic alterations in ulcerative colitis-associated neoplasia focusing onAPC, K-ras gene and microsatellite instability

The status of genetic alterations in ulcerative colitis (UC)-associated neo plasia (UCAN),vas investigated focusing on microsatellite instability (MSI) which is seen in a certain fraction of colorectal carcinomas, and adenomat ous polyposis coli (APC) gene and K-ras gene, in which mutations occur in t he early stage of sporadic colorectal tumorigenesis. Thirty-one UCAN from 1 5 UC patients who had undergone colorectal resection at our institution wer e investigated. There were 8 lesions of invasive carcinoma, 15 high-grade d ysplasia (HGD) and 8 low-grade dysplasia (LGD), DNA was extracted from each neoplastic lesion and corresponding non-neoplastic tissue by a microdissec tion method. MSI status at 9 microsatellite loci, loss of heterozygosity (L OH) at the APC locus, and Ki as codon 12 point mutation were examined, As f or MSI, 4/31 (13%) UCAN (carcinoma: 1/8 (13%), HGD: 2/15 (13%), LGD: 1/8 (1 3%)) were MSI-high (3 or more unstable loci) and 12/31 (39%) UCAN (carcinom a: 3/8 (38%), HGD: 6/15 (40%), LGD: 3/8 (38%)) were MSI-low (1 or 2 unstabl e loci), LOH at the APC locus was not found in 9 UCAN from 6 informative (h eterozygous) cases. The K-ras mutation rate of UCAN was 3/31 (9.7%) (carcin oma: 2/8 (25%), HGD: 1/15 (7%) and LGD: 0/8), MSI is relatively common in U CAN and is present at the early stage of tumorigenesis of UCAN, while the i nvolvement of genetic alterations of the APC gene and K-ras gene is small, MSI may be one of the mechanisms of the increased neoplastic risk in UC, an d UCAN may develop through a different carcinogenic pathway from sporadic c arcinomas.