Influence of methylated p15INK4b and p16INK4a genes on clinicopathological features in colorectal cancer

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Abstract

Background and Aim

Genetic silencing by promoter methylation has attracted attention in the carcinogenesis of colorectal cancer. Methylation of the p16INK4a gene has been found in primary colorectal cancer. Although the p15INK4b gene displays high homology to the p16INK4a gene in the amino acid sequence, methylation of p15INK4b has not been fully studied. We investigated p15INK4b methylation status in patients with colorectal cancer to verify the association between the methylation of p15INK4b and clinicopathological features compared with p16INK4a.

Methods

DNA samples from the tissues of primary colorectal cancer and corresponding adjacent normal colon mucosa were obtained from surgical resections of 88 patients (47 males and 41 females, aged 29–83 years). Methylation-specific polymerase chain reaction was used to analyze p15INK4b and p16INK4a methylation status after bisulfite modification. Cumulative survival rates (mean follow-up period: 53.2 months) were calculated by the Kaplan-Meier analysis.

Results

Methylations of p15INK4b and p16INK4a genes were detected in 23 (26.1%) and 20 (22.7%) colorectal cancers, respectively. Methylation of p15INK4b was not associated with any clinicopathological features. Compared with normal mucosa, the methylation of p15INK4b was more prominent in tumor tissue (P < 0.001). Reverse transcription-polymerase chain reaction (RT-PCR) revealed that p15INK4b methylaton decreased mRNA expression. Kaplan-Meier analysis showed that patients with stage I-II had a significant difference in survival rate between those with and without methylated p15INK4b (P = 0.018).

Conclusions

Our results suggest that methylation of the p15INK4b gene contributes to the process of carcinogenesis in colorectal cancer as well as p16INK4a and is useful as a prognostic factor in the early stage.

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