Aims: Promoter hypermethylation is thought to be a potent mechanism for gene silencing. Hypermethylation of tumor suppressor genes have been reported in a variety of solid tumors. p14ARF and p16INK4a promoter methylation was shown in precancerous lesions associated with chronic inflammation such as Barrett’s esophagus. Little is known about the role of p14ARF and p16INK4a promoter methylation in ulcerative colitis (UC)-related carcinogenesis. Methods: Methylation specific PCR was applied to colectomy specimens or colon resections of 32 UC-patients: 29 samples of nondysplastic mucosa, 9 dysplasias/intraepithelial neoplasias, one adenoma and 36 cancers were tested. Thirty-three sporadic colorectal cancers, matched for UICC tumor stage, grade and location were used as a control group. Results: p14ARF methylation was observed in 3 of 36 (8.3%) UC-related cancers, 2 of 9 (22.2%) dysplasias/intraepithelial neoplasias and 5 of 29 (17.2%) nondysplastic UC-mucosa specimens. In contrast, 16 of 33 (48.4%) of the sporadic cancers showed p14ARF methylation. p16INK4a promoter hypermethylation was found in 26 of 36 (72.2%) of UC-related cancers, 1 of 9 (11.2) dysplasias/intraepithelial neoplasias and 14 of 29 (48.2%) nondysplastic UC-mucosa specimens. In sporadic colorectal cancers, p16INK4a methylation was found in 16 of 33 (48.4%) samples. Conclusions: Our data suggest that methylation of the p16INK4a promoter is a frequent and early event in UC-related carcinogenesis, occuring in one half of UC-nondysplastic mucosa and almost 75% of the cancers. p16INK4a methylation was more frequent in UC-related than in sporadic cancers. p14ARFmethylation, although occuring in 17% of the nondysplastic UC-mucosa specimens and 22.2% of the dysplasias, is infrequent in UC-related cancers, and thus may not play a pivotal role in UC-related carcinogenesis. In sporadic colorectal cancer, p14ARFmethylation is significantly more frequent than in UC-related cancers, indicating an important role for p14ARFmethylation in sporadic carcinogenesis.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]