The global histone modification pattern correlates with cancer recurrence and overall survival in gastric adenocarcinoma

Abstract

Background: Epigenetic alterations such as DNA methylation and histone modification play important roles in carcinogenesis. It has been recently suggested that global histone modification patterns are independent predictors of cancer recurrence. In this study, we used immunohistochemistry to evaluate the patterns of histone H3 and H4 acetylation and trimethylation in gastric adenocarcinomas.

Methods: Double 2-mm core tissue microarrays were made from 261 paraffin-embedded gastric adenocarcinoma samples and examined by immunohistochemistry for histone H3 lysine 9 (H3K9) acetylation and trimethylation, histone H4 lysine 16 acetylation, and histone H4 lysine 20 trimethylation. Sections were graded according to the proportion of tumor cells showing nuclear staining.

Results: Trimethylation of H3K9 positively correlated with tumor stage (P = 0.043); lymphovascular invasion (P = 0.029), cancer recurrence (P = 0.043), and higher level of H3K9 trimethylation correlated with a poor survival rate (P = 0.008). Multivariate survival analysis showed that H3K9 trimethylation status is an independent prognostic factor (P = 0.014). After categorizing cases according to the dominant modification pattern, we found that methylation dominance was associated with lymphovascular invasion (P = 0.001), cancer recurrence (P = 0.001), and poor survival rate (P = 0.028). Methylation dominance was also an independent prognostic factor (P = 0.026) in multivariate survival analysis.

Conclusion: The pattern of histone modification as detected by immunohistochemistry may be useful as a predictor for the recurrence of cancer and may be an independent prognostic factor in gastric adenocarcinomas.