CpG ISLAND METHYLATION and CHROMOSOME 1P LOSS IN ABERRANT CRYPT FOCI

Aberrant crypt foci (ACF) are postulated to be the earliest precursor in colorectal carcinogenesis. CpG island methylator phenotype has been described as another pathway for colorectal cancer. We studied CpG island methylation (CIM) at p16, MINT1, MINT2, MINT31, MGMT, and hMLH1, loss of heterozygosity at chromosome 1p, K-ras mutation, and microsatellite instability in 27 ACF from patients with familial adenomatous polyposis (FAP) and 34 ACF from patients with sporadic colorectal cancer (CRC). CIM was present in 33% (21 of 61) of ACF: 2% at three loci, 13% at two loci and 20% at one locus. K-ras mutation and chromosome 1p loss were present in 25% (15 of 61) and 10% (3 of 31) of ACF, respectively. K-ras mutations (P = 0.007) and chromosome 1p loss (P = 0.01) were more common in ACF with CIM. CIM (P = 0.03) and K-ras mutation (P = 0.01) were more common in ACF from sporadic patients. Methylation and chromosome 1p loss are early event in the pathogenesis of colorectal carcinomas, and ACF from FAP patients and patients with sporadic CRC have distinct phentoypic, genetic and epigenetic changes.