Lack of topoisomerase copy number changes in patients with de novo and relapsed diffuse large B-cell lymphoma

TY - JOUR

T1 - Lack of topoisomerase copy number changes in patients with de novo and relapsed diffuse large B-cell lymphoma

AU - Pedersen, Mette Ø

AU - Poulsen, Tim S

AU - Gang, Anne O

AU - Knudsen, Helle

AU - Lauritzen, Anne F

AU - Pedersen, Michael

AU - Nielsen, Signe L

AU - Brown, Peter

AU - Høgdall, Estrid

AU - Nørgaard, Peter

N1 - Copyright © 2015 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - Topoisomerase (TOP) gene copy number changes may predict response to treatment with TOP-targeting drugs in cancer treatment. This was first described in patients with breast cancer and is currently being investigated in other malignant diseases. TOP-targeting drugs may induce TOP gene copy number changes at relapse, with possible implications for relapse therapy efficacy. TOP gene alterations in lymphoma are poorly investigated. In this study, TOP1 and TOP2A gene alterations were investigated in patients with de novo diffuse large B-cell lymphoma (DLBCL) (n = 33) and relapsed DLBCL treated with chemotherapy regimens including TOP2-targeting drugs (n = 16). No TOP1 or TOP2A copy number changes were found. Polysomy of chromosomes 20 and 17 was seen in 3 of 25 patients (12%) and 2 of 32 patients (6%) with de novo DLBCL. Among relapsed patients, chromosome polysomy was more frequently observed in 5 of 13 patients (38%) and 4 of 16 patients (25%) harboring chromosome 20 and 17 polysomy, respectively; however, these differences only tended to be significant (p = 0.09 and p = 0.09, respectively). The results suggest that TOP gene copy number changes are very infrequent in DLBCL and not likely induced by TOP2-targeting drugs. Increased polyploidy of chromosomes 17 and 20 among patients with relapsed DLBCL may reflect genetic compensation in the tumor cells after TOP2 inhibition, but is more likely due to the increased genetic instability often seen in progressed cancers. Therefore, it is unlikely that TOP1 and TOP2A gene alterations can be used as predictive markers for response to treatment with TOP2-targeting drugs in patients with DLBCL.

AB - Topoisomerase (TOP) gene copy number changes may predict response to treatment with TOP-targeting drugs in cancer treatment. This was first described in patients with breast cancer and is currently being investigated in other malignant diseases. TOP-targeting drugs may induce TOP gene copy number changes at relapse, with possible implications for relapse therapy efficacy. TOP gene alterations in lymphoma are poorly investigated. In this study, TOP1 and TOP2A gene alterations were investigated in patients with de novo diffuse large B-cell lymphoma (DLBCL) (n = 33) and relapsed DLBCL treated with chemotherapy regimens including TOP2-targeting drugs (n = 16). No TOP1 or TOP2A copy number changes were found. Polysomy of chromosomes 20 and 17 was seen in 3 of 25 patients (12%) and 2 of 32 patients (6%) with de novo DLBCL. Among relapsed patients, chromosome polysomy was more frequently observed in 5 of 13 patients (38%) and 4 of 16 patients (25%) harboring chromosome 20 and 17 polysomy, respectively; however, these differences only tended to be significant (p = 0.09 and p = 0.09, respectively). The results suggest that TOP gene copy number changes are very infrequent in DLBCL and not likely induced by TOP2-targeting drugs. Increased polyploidy of chromosomes 17 and 20 among patients with relapsed DLBCL may reflect genetic compensation in the tumor cells after TOP2 inhibition, but is more likely due to the increased genetic instability often seen in progressed cancers. Therefore, it is unlikely that TOP1 and TOP2A gene alterations can be used as predictive markers for response to treatment with TOP2-targeting drugs in patients with DLBCL.

KW - Aneuploidy

KW - Antibodies, Monoclonal, Murine-Derived

KW - Antigens, Neoplasm

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Chromosomes, Human, Pair 17

KW - Chromosomes, Human, Pair 20

KW - Cyclophosphamide

KW - DNA Topoisomerases, Type I

KW - DNA Topoisomerases, Type II

KW - DNA-Binding Proteins

KW - Doxorubicin

KW - Etoposide

KW - Gene Dosage

KW - Humans

KW - In Situ Hybridization, Fluorescence

KW - Lymphoma, Large B-Cell, Diffuse

KW - Neoplasm Proteins

KW - Prednisolone

KW - Prednisone

KW - Recurrence

KW - Rituximab

KW - Topoisomerase II Inhibitors

KW - Vincristine

U2 - 10.1016/j.exphem.2015.04.006

DO - 10.1016/j.exphem.2015.04.006

M3 - Journal article

C2 - 25931012

SN - 0301-472X

VL - 43

SP - 534

EP - 536

JO - Experimental Hematology

JF - Experimental Hematology

IS - 7

ER -