Grade I, II and III Follicular Lymphomas Express Ig V H Genes with Different Patterns of Somatic Mutation
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ORIGINAL ARTICLE
Grade I, II and III Follicular Lymphomas Express Ig VH Genes with Different Patterns of Somatic Mutation Balázs Csernus 1
&
Botond Timár 1 & Zsolt Fülöp 1 & András Matolcsy 1,2
Received: 26 May 2020 / Accepted: 10 June 2020 # The Author(s) 2020
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. Keywords Follicular lymphoma| . Immunoglobulin gene . Somatic mutation . Clonal evolution
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. Morphologically, FLs are composed of a mixture of centrocytes (small cleaved cells) and centroblasts (large noncleaved cells) which grow in a highly organized nodular/ Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12253-020-00843-x) contains supplementary material, which is available to authorized users. * András Matolcsy [email protected] 1
1st Department of Pathology and Experimental Cancer Research, Faculty of Medicine, Semmelweis University, Üllői út 26, Budapest 1085, Hungary
2
Department of Laboratory Medicine, Karolinska Institute, Solna, Sweden
follicular pattern [1–3]. Based on the proportion of centroblasts within the neoplastic follicles, FLs can be classifi
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