Profiling of biological and environmental risk factors in immunogenetic subgroups of chronic lymphocytic leukemia - Czech national study.

Kamila Stranska,Lukas Smolej,Karla Plevova,Sarka Pospisilova,Anna Panovska,Michael Doubek,Martin Spacek,Jana Zuchnicka,Martin Simkovic,Yvona Brychtova,Renata Urbanova,Jiri Mayer,Lenka Radova,Magdalena Von Jagwitz-Biegnitz,Stanislava Hrobkova,Hana Skabrahova,Hana Skuhrova Francova,Lekaa Mohammadova

doi:10.5507/bp.2019.046

Abstract

This is a nation-wide survey of chronic lymphocytic leukemia (CLL) patients at six large hematology centers in the Czech Republic. The aim was to identify specific populations, social, and health characteristics of CLL subgroups divided according to the immunogenetic features of their B cell receptors (BCRs) and clonality. Questionnaires directed to specific health, social, and environmental conditions were collected in a cohort of 573 CLL patients. For these patients, immunoglobulin heavy chain gene rearrangements were also analyzed in order to gain information about their clonality, IGHV mutational status, and the presence of stereotyped BCRs. Data extracted from the questionnaires were analyzed statistically in the context of immunogenetic features of the cohort. There were no statistically significant differences in the data collected in the survey between patients with mutated and patients with unmutated IGHV. However, patients with oligoclonal CLL reported health conditions such as hypercholesterolemia, hypertension, herpes simplex, tumors, and also, separately, CLL in 1st degree relatives, more often than their monoclonal counterparts. In patients with stereotyped BCRs, we found more frequent alcohol consumption and gastric infections in subset #1 cases and frequent cholecystectomies and familial CLL in subset #2 cases. To the best of our knowledge, this study is the first to investigate CLL immunogenetic features and clonality in the context of epidemiological data. We reported statistically significant associations suggesting the influence of certain health and social conditions on a number of clonal populations expanding in CLL and also on characteristic BCR features, especially stereotypy.

Highlights

Chronic lymphocytic leukemia (CLL) is characterized by extraordinary heterogeneity in clinical presentation, disease course and molecular features of malignant B cells
Since CLL is a clonal disease of mature B cells, each case can be described by a unique set of IG rearrangements that encode for the B-cell receptor (BCR)
CLL BCRs with mutated IG heavy chain variable region (IGHV) and those with unmutated IGHV differ in the level of their responsiveness to stimulation, with mutated BCRs showing reduced activation of the signaling response, and in interactions with antigens, with unmutated BCRs being more polyreactive and more frequently binding autoantigens[15,29,30]

Summary

Introduction

Chronic lymphocytic leukemia (CLL) is characterized by extraordinary heterogeneity in clinical presentation, disease course and molecular features of malignant B cells. Many factors influence disease onset and course, some of which are currently used as prognostic or predictive markers These involve specific chromosomal abnormalities[1], protein expression levels[2,3,4,5], gene mutations[6,7,8,9,10], epigenetic changes[10], microRNA deregulation[11], or molecular features of immunoglobulin (IG) gene rearrangements[2,12,13]. The striking degree of BCR sequence similarity observed between unrelated cases in one-third of patients[16] suggests promoting pressure leading to CLL clone selection caused by a shared set of antigen epitopes. In this context, various antigens/epitopes recognized by CLL BCRs have been described. Expansion of multiple clones in such cases raises the question of whether these clones might proliferate upon chronic stimulation by antigens present in a case

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Conclusion