Integrative NGS testing reveals clonal dynamics of adverse genomic defects contributing to a natural progression in treatment-naïve CLL patients

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Authors

NAVRKALOVÁ Veronika PLEVOVÁ Karla RADOVÁ Lenka PORC Jakub Paweł PÁL Karol MALČÍKOVÁ Jitka PAVLOVÁ Šárka DOUBEK Michael PANOVSKÁ Anna KOTAŠKOVÁ Jana POSPÍŠILOVÁ Šárka

Year of publication 2024
Type Article in Periodical
Magazine / Source British journal of haematology
MU Faculty or unit

Central European Institute of Technology

Citation
Web https://onlinelibrary.wiley.com/doi/epdf/10.1111/bjh.19191
Doi http://dx.doi.org/10.1111/bjh.19191
Keywords chronic lymphocytic leukaemia; clonal evolution; genomic aberration; integrative NGS testing; prognosis
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Description Large-scale next-generation sequencing (NGS) studies revealed extensive genetic heterogeneity, driving a highly variable clinical course of chronic lymphocytic leukaemia (CLL). The evolution of subclonal populations contributes to diverse therapy responses and disease refractoriness. Besides, the dynamics and impact of subpopulations before therapy initiation are not well understood. We examined changes in genomic defects in serial samples of 100 untreated CLL patients, spanning from indolent to aggressive disease. A comprehensive NGS panel LYNX, which provides targeted mutational analysis and genome-wide chromosomal defect assessment, was employed. We observed dynamic changes in the composition and/or proportion of genomic aberrations in most patients (62%). Clonal evolution of gene variants prevailed over the chromosomal alterations. Unsupervised clustering based on aberration dynamics revealed four groups of patients with different clinical behaviour. An adverse cluster was associated with fast progression and early therapy need, characterized by the expansion of TP53 defects, ATM mutations, and 18p- alongside dynamic SF3B1 mutations. Our results show that clonal evolution is active even without therapy pressure and that repeated genetic testing can be clinically relevant during long-term patient monitoring. Moreover, integrative NGS testing contributes to the consolidated evaluation of results and accurate assessment of individual patient prognosis.
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