Clonal relationships in recurrent B-cell lymphomas.

Seung Eun Lee,Hae Yong Yoo,Seok Jin Kim,Young Hyeh Ko,So Young Kang,Won Seog Kim

doi:10.18632/oncotarget.7132

Abstract

Immunoglobulin (Ig) gene rearrangements remain largely unmodified during the clonal expansion of neoplastic cells. We investigated the clonal relationships between lymphoma components at diagnosis and at relapse by analyzing Ig gene rearrangements. A BIOMED-2 multiplex polymerase chain reaction (PCR) assay was performed in 27 patients using formalin-fixed paraffin embedded tissues, with subsequent cloning and sequencing of the amplified Ig genes in 17 patients. All 27 cases of primary and corresponding relapsed tumors showed monoclonal rearrangements of the Ig genes by BIOMED-2 PCR. Whereas IgVH or IgVK fragment lengths were identical in 8/27 pairs (30%), fragment lengths differed in 19/27 pairs (70%). In 17 cases analyzed by sequencing, an identical VDJ gene rearrangement was confirmed in 4/4 pairs (100%) with the same fragment lengths and in 10/13 pairs (77%) with different fragment lengths. Four of 17 primary lymphomas had multiple VDJ rearrangements, and three of them showed an unrelated relapse. Unrelated relapse was observed in 1/8 mantle cell lymphomas, 1/5 diffuse large B-cell lymphomas, and a large B cell lymphoma developed in a patient with a small lymphocytic lymphoma. Unrelated relapses developed after a longer disease-free interval and tended to show poorer outcome compared with related relapse. In summary, relapse of a lymphoma from an unrelated clone is uncommon, but can occur in B-cell lymphomas. Clonal relationships should be determined by sequencing of the Ig genes, and not just by comparing the PCR product size.

Highlights

Despite recent advances in therapeutic strategies for non-Hodgkin’s lymphoma (NHL), a significant proportion of patients relapse, or their tumors are refractory to treatments [1]
To investigate the clonal identity of lymphoma cells in primary and corresponding relapsed tumors, we focused on VDJ rearrangements using BIOMED-2 multiplex polymerase chain reaction (PCR) assays in 27 pairs of matched primary and relapsed B-cell lymphomas together with sequencing of the amplified Ig genes
Patients who relapsed at 3–12 months after receiving treatment for a primary B-cell lymphoma were considered as having an early relapse

Summary

Introduction

Despite recent advances in therapeutic strategies for non-Hodgkin’s lymphoma (NHL), a significant proportion of patients relapse, or their tumors are refractory to treatments [1]. One of the most important questions regarding relapses is whether they represent true, clonally related diseases or unrelated second lymphomas arising de novo. Because the management of both tumor types should be different, distinguishing between recurrent B-cell lymphomas and second primary lymphomas has clinical importance. In high-grade tumors, high-dose chemotherapy followed by autologous hematopoietic stem-cell transplantation has become the standard of care for patients with their first relapse of NHL [2]. A second de novo lymphoma might be treated with first-line therapy. It is not possible to distinguish such unrelated second lymphomas from clonally related lymphomas from clinical data and histopathology

Objectives

Methods

Results

Conclusion