DNA methyltransferase DNMT3b protein overexpression as a prognostic factor in patients with diffuse large B-cell lymphomas

Abstract

Diffuse large B-cell lymphomas (DLBCL) are the most common type of aggressive lymphomas, with considerable heterogeneity in clinical presentation, molecular characteristics, and outcome. Previous studies have showed significant correlations between DNA methyltransferase (DNMT) overexpression and unfavorable prognosis in human cancers. Therefore, we investigated in this study the biological and prognostic significance of DNMT1, DNMT3a, and DNMT3b protein expression in DLBCL. DNA methyltransferase (DNMT) expression was analyzed by immunohistochemistry in 81 DLBCL cases and correlated with clinicopathological parameters. Kaplan-Meier curves were used to estimate survival rates, and the Cox proportional hazard regression model was used to evaluate the prognostic impact of DNMT expression. Our results showed that overexpression of DNMT1, DNMT3a, and DNMT3b were detected in 48%, 13%, and 45% of investigated cases, respectively. DNA methyltransferase 1 (DNMT1) and DNMT3b overexpression was significantly correlated with advanced clinical stages (P = 0.028 and P = 0.016, respectively). Moreover, concomitant expression of DNMT1 and DNMT3b was significantly correlated with resistance to treatment (P = 0.015). With regard to survival rates, although data was available only for 40 patients, DNMT3b overexpression was significantly correlated with shorter overall survival (P = 0.006) and progression-free survival (P = 0.016). Interestingly, multivariate analysis demonstrated that DNMT3b overexpression was an independent prognostic factor for predicting shortened overall survival (P = 0.004) and progression-free survival (P = 0.024). In conclusion, DNMT3b overexpression was identified as an independent prognostic factor for predicting shortened survival of patients with DLBCL and could be, therefore, useful in identifying patients who would benefit from aggressive therapy.

Figure 1

Immunohistochemical staining patterns of DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b proteins expression in diffuse large B‐cell lymphomas. (a,c,e) Representative examples of positive immunostaining for DNMT1, DNMT3a, and DNMT3b expression, respectively. (b,d,f) Repre‐sentative examples of negative immunostaining for DNMT1, DNMT3a, and DNMT3a expression, respectively.

Figure 2

Kaplan–Meier analyses of overall survival and disease‐free survival in diffuse large B‐cell lymphomas with respect to DNA methyltransferase 1 (DNMT1), DNMT3a, and DNMT3b protein overexpression. Survival curves show that DNMT3b overexpression was significantly correlated with poorer overall survival (P = 0.006; [e]) and progression‐free survival (P = 0.016; [f]), whereas no significant difference was seen in overall survival or disease‐free survival between patients showing normal or overexpression of DNMT1 (a,b) or DNMT3a (c,d).