Mucinous colorectal cancer (CRC) has been reported to have distinct clinicopathological and genetic characteristics. However, the incidence and the relationship among microsatellite instability (MSI), CpG island methylator phenotype (CIMP) and BRAF and KRAS mutations in mucinous and non-mucinous CRC are not known. Activating mutations of BRAF and KRAS and their relationship with MSI and CIMP were examined in 83 sporadic CRC specimens (26 mucinous and 57 non-mucinous CRC). MSI, CIMP, BRAF and KRAS mutation were observed in 17, 24, 25 and 36% of the tumors, respectively. BRAF mutation was highly correlated with MSI (p < 0.001) and CIMP (p < 0.001). A higher incidence of MSI (27% vs. 12%), CIMP (38% vs. 18%, p < 0.05) and BRAF mutation (46% vs. 16%, p < 0.01) was observed in mucinous CRC. KRAS mutation (27% vs. 40%) was observed more frequently in non-mucinous CRC. Significantly higher percentages of mucinous CRC (54%, p < 0.05) had MSI or CIMP or BRAF mutations. Concordant occurrence of 2 or more of these alterations was observed in 39% of mucinous CRC and only 11% of non-mucinous CRC (p < 0.01). The more frequent occurrence and closer association among MSI, CIMP and BRAF mutation in mucinous CRC observed in our study further supports the idea that its pathogenesis may involve distinct genetic and epigenetic changes. ' 2005 Wiley-Liss, Inc.Key words: mucinous colorectal cancer; microsatellite instability; CpG island methylator phenotype; BRAF mutation; KRAS mutation Colorectal cancer (CRC) develops as a result of progressive accumulation of genetic and epigenetic alterations.1 There are at least 2 major genetic instability pathways involved in colorectal carcinogenesis, chromosomal instability and microsatellite instability (MSI).2,3 The chromosomal instability pathway is found in about 80% of CRCs. 4 This pathway involves chromosomal aberrations such as loss of heterozygosity of 5q, 17p and 18q, with inactivation of APC, p53 and DCC genes.2 MSI, a second form of genetic instability, is found in most cases of hereditary non-polyposis colorectal cancer (HNPCC) and in about 15% of sporadic CRCs. [5][6][7] This pathway involves inactivation of DNA mismatch repair genes followed by mutations in mononuclear tracts in the coding region of genes implicated in tumor progression such as TGFbRII and BAX, which leads to uncontrolled growth and decreased apoptosis.8-10 Chromosomal aberrations are rare in microsatellite unstable tumors. Recently, additional pathways involving epigenetic abnormalities have been described. 11,12 These include CpG island methylator phenotype (CIMP) with hypermethylation of CpG islands in the promoter regions of multiple genes such as p16, p14, MGMT and hMLH1, causing transcriptional inactivation of these genes. 13CIMP is found in 20-32% of sporadic CRC and has been frequently associated with MSI through methylation of hMLH1 promoter region. 12,[14][15][16] The RAS/RAF/MAP kinase cascade is an important pathway that mediates the cellular response to extracellular signals, which regulate cell grow...

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Purpose: The relationship between global hypomethylation, chromosomal instability (CIN), and microsatellite instability (MSI) remains unclear in colorectal cancer. The aim of this study was to investigate the relationship between global methylation status, loss of heterozygosity (LOH), and MSI in sporadic colorectal cancer. Experimental Design: We determined global methylation levels in 80 sporadic colorectal cancers, 51adjacent normal tissues, and 20 normal tissues using the long interspersed nucleotide elements^combined bisulfite restriction analysis method. We also analyzed 80 colorectal cancers for MSI status and LOH at chromosomes 5q21, 8p12-22, 17p13, and 18q21. Results: We identified 14 cases of MSI (17.5 %) and 58 cases of LOH (72.5 %). LOH was observed more frequently in microsatellite stable (MSS) cancers than in MSI cancers at all loci. Colorectal cancers showed significantly lower global methylation levels than did normal tissues (41.0 F 9.7% versus 54.3 F 6.5%; P < 0.001). MSS cancers showed significantly lower global methylation levels when compared with MSI cancers (39.5 F 9.4% versus 48.2 F 8.2 %; P = 0.003). Tumors with global hypomethylation (with V40% of methylation levels) had a significantly increased number of chromosomal loci with LOH than did tumors without global hypomethylation (1.9 versus 0.9; P < 0.001); 11tumors (13.9%) lacked both MSI and LOH. This subgroup had significantly higher global methylation levels (46.8 F 8.7%) than did MSS cancers with LOH (38.0 F 9.0%; P = 0.006). Conclusions:These data showed a significant association between global hypomethylation and chromosomal instability in sporadic colorectal cancer. This suggests that global hypomethylation plays an important role in inducing genomic instability in colorectal carcinogenesis.