Microsatellite instability-low colorectal cancer acquires a KRAS mutation during the progression from Dukes' A to Dukes' B

Abstract

The classification of colorectal cancer (CRC) by microsatellite instability (MSI) status is important for effective clinical management. In fact, microsatellite instability-high (MSI-H) cancer has distinctive clinicopathological and molecular features. However, microsatellite instability-low (MSI-L) cancer is not clearly defined. The objective of this study was to further clarify the characteristics of MSI-L CRC. A consecutive series of 940 primary CRCs were subdivided into three groups according to the level of MSI and analyzed the clinicopathological features and genetic changes in the KRAS, BRAF and p53 mutation and the loss of heterozygosity (LOH) of adenomatous polyposis coli (APC) gene and methylation status of the O(6)-methylguanine-DNA methyltransferase (MGMT) and MLH1 promoter. Of the 940 CRCs, 5.9% were MSI-H, 7.1% were MSI-L and 87% were microsatellite stable (MSS). KRAS and BRAF mutations were detected in 39.4 and 4.6% of the CRCs, respectively. The frequency of KRAS mutations in MSI-H, MSI-L and MSS cancer was 30, 48 and 39%, respectively. The proportion of KRAS mutations in MSI-L cancer increased from 16 to 63% accompanying the progression from Dukes' A to Dukes' B. While the LOH of D5S346, which is located near the APC gene, and p53 mutation was observed in 75 and 67% of MSI-L CRC at Dukes' A, respectively. These results indicated that the LOH of APC and p53 mutation has already occurred by the Dukes' A lake 'suppressor pathway' but not the KRAS mutation in MSI-L CRCs. The genes involving MSI-L carcinogenesis are similar to MSS but the timing and frequency of the KRAS mutation is different.