The Prognostic Significance of Global Histones Deacetylation in Colorectal Cancer Patients Treated with Fluoropyrimdine Therapy

Abstract

To study the impact of fluoropyrimidine (FP)- therapy on the acetylation level of histones (H3 and H4), and its correlation to treatment outcome in colorectal cancer (CRC) patients. Total histone protein was extracted, and the level of global histones (H3 and H4) acetylation was determined in the peripheral blood of 66 CRC patients before treatment with FP therapy, and also in 48 and 32 of those patients after 3 and 6 months of treatment, respectively. Clinicopathological stratification of patients was conducted for subgroup analysis. After three years of follow up, event-free survival (EFS) and the hazard of recurrence and progression were determined by Kaplan –Meier and COX regression analyses, respectively. Baseline CRC patients showed global H3 hyperacetylation by 160%, but H4 hypoacetylation by 87% relative to healthy control. FP therapy significantly reduced global H3 and H4 acetylation levels especially in subgroups of CRC patients > 45 years, females, with right colon tumours, with normal baseline levels of CEA and CA19.9, with negative lymph nodes and negative metastasis, and also in the patients who showed no signs of recurrence or progression after three years of follow up. Survival analyses showed decreased median EFS time and increased the hazard of recurrence and progression in patients with high CEA (HR= 3.38, P= 0.023), positive metastasis (HR= 1.16, P<0.001), and H4 hypoacetylation <87% (HR= 1.55, P=0.014). FP therapy-induced reduction in the global level of histones acetylation declared in subgroups of CRC patients with excellent prognostic features.