Carcinogenesis Advance Access published online on January 15, 2009
Carcinogenesis, doi:10.1093/carcin/bgp017
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Microsatellite instability-low colorectal cancer acquires a KRAS mutation during the progression from Dukes’ A to Dukes’ B.
1 Division of Molecular Diagnosis and Cancer Prevention
2 Division of Gastroenterological Surgery
3 Division of Gastroenterology, Saitama Cancer Center, 818 Komuro Ina, Kitaadachigun, Saitama 362-0806, Japan
* To whom correspondence should be addressed. Kiwamu Akagi, M.D., Ph.D., Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, 818 Komuro Ina, Kitaadachigun, Saitama 362-0806, Japan, Tel: +81-48-722-1111, Fax: +81-48-723-5197, E-mail: akagi{at}cancer-c.pref.saitama.jp
The classification of colorectal cancer (CRC) by microsatellite instability (MSI) status is important for effective clinical management. In fact, MSI-high (MSI-H) cancer has distinctive clinicopathological and molecular features. However, MSI-low (MSI-L) cancer is not clearly defined. The objective of this study was to further clarify the characteristics of MSI-L colorectal cancer. A consecutive series of 940 primary colorectal cancers were subdivided into 3 groups according to the level of MSI and analyzed the clinicopathological features and genetic changes in the KRAS, BRAF and p53 mutation and the LOH of APC and methylation status of the MGMT and MLH1 promoter. Of the 940 colorectal cancers, 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.
Key Words: microsatellite instability • KRAS • BRAF • MSI-L • tumor progression
Received October 20, 2008; revised January 7, 2009; accepted January 8, 2009.