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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\u2010wide 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 <jats:italic>TP53<\/jats:italic> defects, <jats:italic>ATM<\/jats:italic> mutations, and 18p\u2212 alongside dynamic <jats:italic>SF3B1<\/jats:italic> mutations. Our results show that clonal evolution is active even without therapy pressure and that repeated genetic testing can be clinically relevant during long\u2010term patient monitoring. Moreover, integrative NGS testing contributes to the consolidated evaluation of results and accurate assessment of individual patient prognosis.<\/jats:p>","DOI":"10.1111\/bjh.19191","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T02:03:13Z","timestamp":1702000993000},"page":"240-249","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative NGS testing reveals clonal dynamics of adverse genomic defects contributing to a natural progression in treatment\u2010na\u00efve CLL patients"],"prefix":"10.1111","volume":"204","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3020-1578","authenticated-orcid":false,"given":"Veronika","family":"Navrkalova","sequence":"first","affiliation":[{"name":"Department of Internal Medicine \u2013 Hematology and Oncology University Hospital Brno and Faculty of Medicine Masaryk University  Brno Czech Republic"},{"name":"Center of Molecular 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