Grade I, II and III Follicular Lymphomas Express Ig VH Genes with Different Patterns of Somatic Mutation

András Matolcsy ,Zsolt Zoltán Fülöp ,Balázs Csernus ,Botond Tímár

doi:10.1007/s12253-020-00843-x

András Matolcsy , Zsolt Zoltán Fülöp

Open Access

https://doi.org/10.1007/s12253-020-00843-x

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Abstract

Follicular lymphoma (FL) is an indolent, B-cell, non-Hodgkin’s lymphoma with varying cytological appearance and clinical behavior. The genetic hallmark of FL is the t(14;18) translocation, and as a germinal center derived entity it is also characterized by somatic hypermutation of the immunoglobulin heavy chain (IgH) gene. In an attempt to correlate this molecular signature with the cytological grading of FL, we have analyzed the IgH variable (IgVH), regions in all cytological grades of FL. Four FL cases showing t(14;18) translocation were classified into grade I-III categories according to the current WHO guidelines. The IgVH gene segments were PCR-amplified, sequenced, and compared to their respective germline IgVH sequences. The neoplastic cells of grade I and II FLs revealed clonally related, but highly divergent IgVH gene sequences indicating the ongoing nature of somatic hypermutation. Grade III FL also showed extensive presence of somatic hypermutation, but these mutations were not associated with intraclonal divergence. Thus, these results suggest that grade I-II and grade III FL may represent different biological entities. The presence of ongoing somatic hypermutation of IgVH sequences in grade I and II FLs is compatible with direct follicular origin of these tumor cells, contrasting the homogenous, stable clones of grade III FL resembling a post-follicular stage of B-cell development. Our findings demonstrate that contrary to the three tiered cytological grading, molecular features of IgH genes classify FL into two distinct subcategories. These studies also suggest that with progression FL gains post-follicular–like molecular features and becomes independent of the germinal center microenvironment.

Highlights

Follicular lymphoma (FL) is a predominantly indolent, germinal center derived, B-cell non-Hodgkin’s lymphoma with an overwhelming majority of cases carrying the characteristic t(14;18) translocation
FL can be classified according to the WHO into grade I-III categories based on histological features that correlate with clinical outcome
In our study we have analyzed the sequence of Ig VH-D-JH genes in different histological grades of FL in an attempt to reveal differing molecular signatures correlating with the histological appearance and biological behavior

Summary

Introduction

Follicular lymphoma (FL) is a predominantly indolent, germinal center derived, B-cell non-Hodgkin’s lymphoma with an overwhelming majority of cases carrying the characteristic t(14;18) translocation. B-cell lymphomas are generally considered to originate from B-lymphocytes “frozen” at certain points of their physiological differentiation [10, 11]. In case of follicular lymphomas, the cell of origin is considered to be the B-cells arrested at the germinal center stage of differentiation [12, 13]. This concept is supported by the findings that the immunoglobulin (Ig) genes of FL B-cells are exposed to the hypermutation machinery characterizing the physiological GC reaction. The type and distribution of these somatic IgH mutations indicate the contribution of antigen selection and reflect the clonal evolution of the neoplastic cells [14, 15]

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