P-0100 H4K12 And H3K18 Acetylation Associates with poor Prognosis in Pancreatic Cancer

Abstract

IntroductionEpigenetic deregulation may be involved in tumor cell biology, including cell growth, differentiation, tumor progression and cell death, and histone acetylation is a major regulatory mechanism of gene transcription. Patterns of global histone modifications have been recently suggested as outcome predictors in cancer patients, but few studies have been conducted on pancreatic ductal adenocarcinomas (PDACs). This study was designed to investigate the predictive value of histone acetylation modifications in pancreatic cancer. MethodsA retrospective clinicopathologic analysis was undertaken in all patients diagnosed with PDAC between 2005 and 2011 at our institution, and immunohistochemistry performed with polyclonal antibodies against H4K12ac, H3K9ac and H3K18ac. Semi-quantitative assessment of the percentage of tumor cells with positive nuclear staining (0% to 100%) and intensity of staining (0 to 3+) was performed independently by two pathologists who were blinded to all clinicopathologic and outcome variables. Immunohistochemical staining was also evaluated by the modified Histo-score (H-score), which involves assessment of both the intensity of staining and the percentage of positive cells. Nuclear staining for each histone was further classified into low or high-staining groups. Results were analyzed in relation to patients' clinicopathologic parameters. ResultsA total of 119 patients with pancreatic cancer were included in this study. The median age at diagnosis was 66 years (range, 36-92 years, SD±10.3) and median post-diagnosis follow-up was 14.2 months. Ninety patients (76%) died during the follow-up period. Median percentage of cells staining positive for H4K12ac, H3K9Ac and H3K18ac was 60% (±26.9), 80% (±21.2) and 65% (±24.7), respectively. There was a positive relationship between tumor differentiation and H4K12ac high scores (p<0.05) and staining with the three markers correlated positively with tumor stage (p <0.01). Univariate analysis showed worse survival in patients with high detection levels of H4K12ac (p=0.038) and H3K18Ac (p = 0.033). A backwards Cox proportional hazards model analysis revealed the independent prognostic effect of high H4K12ac and H3K18ac levels (hazard ratios of 1.6 and 1.7 respectively, p <0.05), especially for patients at early stages of disease (I and II). ConclusionHere we demonstrate that two histones modifications, H4K12 and H3K18 acetylation, correlates with worse prognosis and poor survival in pancreatic cancer, being independent prognostic factors for overall survival. The prognostic role of H3K9ac remains elusive, mandating further evaluation. Additional studies of histone modifications in pancreatic cancer can lead to a better comprehension of the epigenetic mechanisms involved in carcinogenesis and provide the information necessary to develop early diagnosis and therapeutics strategies.