DNMT1 is predictive of survival and associated with Ki-67 expression in R-CHOP-treated diffuse large B-cell lymphomas

TY - JOUR

T1 - DNMT1 is predictive of survival and associated with Ki-67 expression in R-CHOP-treated diffuse large B-cell lymphomas

AU - Loo, Suet Kee

AU - Ch'ng, Ewe Seng

AU - Lawrie, Charles H

AU - Muruzabal, María Arestin

AU - Gaafar, Ayman

AU - Pomposo, María Puente

AU - Husin, Azlan

AU - Md Salleh, Md Salzihan

AU - Banham, Alison H

AU - Pedersen, Lars M

AU - Møller, Michael B

AU - Green, Tina M

AU - Wong, Kah Keng

N1 - Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

PY - 2017/12

Y1 - 2017/12

N2 - DNMT1 is a target of approved anti-cancer drugs including decitabine. However, the prognostic value of DNMT1 protein expression in R-CHOP-treated diffuse large B-cell lymphomas (DLBCLs) remains unexplored. Here we showed that DNMT1 was expressed in the majority of DLBCL cases (n = 209/230, 90.9%) with higher expression in germinal centre B-cell-like (GCB)-DLBCL subtype. Low and negative DNMT1 expression (20% cut-off, n = 33/230, 14.3%) was predictive of worse overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001). Nonetheless, of the 209 DNMT1 positive patients, 33% and 42% did not achieve 5-year OS and PFS, respectively, indicating that DNMT1 positive patients showed considerably heterogeneous outcomes. Moreover, DNMT1 was frequently expressed in mitotic cells and significantly correlated with Ki-67 or BCL6 expression (r = 0.60 or 0.44, respectively; p < 0.001). We demonstrate that DNMT1 is predictive of DLBCL patients' survival, and suggest that DNMT1 could be a DLBCL therapeutic target due to its significant association with Ki-67.

AB - DNMT1 is a target of approved anti-cancer drugs including decitabine. However, the prognostic value of DNMT1 protein expression in R-CHOP-treated diffuse large B-cell lymphomas (DLBCLs) remains unexplored. Here we showed that DNMT1 was expressed in the majority of DLBCL cases (n = 209/230, 90.9%) with higher expression in germinal centre B-cell-like (GCB)-DLBCL subtype. Low and negative DNMT1 expression (20% cut-off, n = 33/230, 14.3%) was predictive of worse overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001). Nonetheless, of the 209 DNMT1 positive patients, 33% and 42% did not achieve 5-year OS and PFS, respectively, indicating that DNMT1 positive patients showed considerably heterogeneous outcomes. Moreover, DNMT1 was frequently expressed in mitotic cells and significantly correlated with Ki-67 or BCL6 expression (r = 0.60 or 0.44, respectively; p < 0.001). We demonstrate that DNMT1 is predictive of DLBCL patients' survival, and suggest that DNMT1 could be a DLBCL therapeutic target due to its significant association with Ki-67.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antibodies, Monoclonal, Murine-Derived

KW - Antineoplastic Combined Chemotherapy Protocols

KW - B-Lymphocytes/pathology

KW - Biomarkers, Tumor/metabolism

KW - Cyclophosphamide

KW - DNA (Cytosine-5-)-Methyltransferase 1/metabolism

KW - Disease-Free Survival

KW - Doxorubicin

KW - Female

KW - Germinal Center/pathology

KW - Humans

KW - Ki-67 Antigen/metabolism

KW - Lymphoma, Large B-Cell, Diffuse/diagnosis

KW - Male

KW - Middle Aged

KW - Prednisone

KW - Prognosis

KW - Vincristine

KW - Young Adult

U2 - 10.1016/j.pathol.2017.08.009

DO - 10.1016/j.pathol.2017.08.009

M3 - Journal article

C2 - 29074044

SN - 0031-3025

VL - 49

SP - 731

EP - 739

JO - Pathology

JF - Pathology

IS - 7

ER -