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

Suet Kee Loo; Ewe Seng Ch'ng; Charles H Lawrie; María Arestin Muruzabal; Ayman Gaafar; María Puente Pomposo; Azlan Husin; Md Salzihan Md Salleh; Alison H Banham; Lars M Pedersen; Michael B Møller; Tina M Green; Kah Keng Wong

doi:10.1016/j.pathol.2017.08.009

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

Suet Kee Loo, Ewe Seng Ch'ng, Charles H Lawrie, María Arestin Muruzabal, Ayman Gaafar, María Puente Pomposo, Azlan Husin, Md Salzihan Md Salleh, Alison H Banham, Lars M Pedersen, Michael B Møller, Tina M Green, Kah Keng Wong

Institut for Klinisk Medicin

9 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Tidsskrift	Pathology
Vol/bind	49
Udgave nummer	7
Sider (fra-til)	731-739
ISSN	0031-3025
DOI	https://doi.org/10.1016/j.pathol.2017.08.009
Status	Udgivet - dec. 2017

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Loo, S. K., Ch'ng, E. S., Lawrie, C. H., Muruzabal, M. A., Gaafar, A., Pomposo, M. P., Husin, A., Md Salleh, M. S., Banham, A. H., Pedersen, L. M., Møller, M. B., Green, T. M., & Wong, K. K. (2017). DNMT1 is predictive of survival and associated with Ki-67 expression in R-CHOP-treated diffuse large B-cell lymphomas. Pathology, 49(7), 731-739. https://doi.org/10.1016/j.pathol.2017.08.009

@article{f99c607d01f9497e87aff83204fb8c2b,

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

abstract = "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.",

keywords = "Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Combined Chemotherapy Protocols, B-Lymphocytes/pathology, Biomarkers, Tumor/metabolism, Cyclophosphamide, DNA (Cytosine-5-)-Methyltransferase 1/metabolism, Disease-Free Survival, Doxorubicin, Female, Germinal Center/pathology, Humans, Ki-67 Antigen/metabolism, Lymphoma, Large B-Cell, Diffuse/diagnosis, Male, Middle Aged, Prednisone, Prognosis, Vincristine, Young Adult",

author = "Loo, {Suet Kee} and Ch'ng, {Ewe Seng} and Lawrie, {Charles H} and Muruzabal, {Mar{\'i}a Arestin} and Ayman Gaafar and Pomposo, {Mar{\'i}a Puente} and Azlan Husin and {Md Salleh}, {Md Salzihan} and Banham, {Alison H} and Pedersen, {Lars M} and M{\o}ller, {Michael B} and Green, {Tina M} and Wong, {Kah Keng}",

year = "2017",

month = dec,

doi = "10.1016/j.pathol.2017.08.009",

language = "English",

volume = "49",

pages = "731--739",

journal = "Pathology",

issn = "0031-3025",

publisher = "Lippincott Williams & Wilkins, Ltd.",

number = "7",

}

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

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 -

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

Abstract

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