The relationship between global methylation level, loss of heterozygosity, and microsatellite instability in sporadic colorectal cancer.

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, 51 adjacent 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+/-9.7% versus 54.3+/-6.5%; P<0.001). MSS cancers showed significantly lower global methylation levels when compared with MSI cancers (39.5+/-9.4% versus 48.2+/-8.2%; P=0.003). Tumors with global hypomethylation (with <or=40% 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); 11 tumors (13.9%) lacked both MSI and LOH. This subgroup had significantly higher global methylation levels (46.8+/-8.7%) than did MSS cancers with LOH (38.0+/-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.