Skewing of the BcR IGH gene repertoire is detectable by next-generation sequencing up to 16 years before CLL diagnosis. Dominant clonotype frequency represents the size of the largest (most frequent) productive clonotype as a percentage of the total productive IGH gene reads in each given sample. Time to diagnosis for controls reflects the time from sampling of the control to the diagnosis of the matched case. One sample was taken from each patient. (A) Dominant clonotype frequency for patients with CLL and matched controls over time to CLL diagnosis. (B) Positive correlation between time to diagnosis (TTD) and the dominant clonotype frequency as determined by Spearman correlation. The red line represents Loess regression, with 95% confidence intervals (CIs) marked around. (C) Kaplan-Meier (survival) analysis for TTD from prediagnostic sample collection stratified by clonotype frequency. TTD of patients with a dominant clonotype frequency ≥2% of the productive IGH gene repertoire is depicted in red, whereas TTD of patients with a dominant clonotype frequency <2% is depicted in blue. The 95% CI is marked for each line. Significance was determined by the log-rank test. (D) Lymphocyte counts in patients with future CLL and matched controls. (E) Dominant clonotype frequency for the same samples and individuals as in panel D. (F) Lymphocyte counts plotted against dominant clonotype frequency. The lymphocyte count of 1 outlier at 45 × 10⁹/L was winsorized to 20 × 10⁹/L to preserve visibility of low-level dynamics. Dashed line indicates cutoff for abnormal lymphocyte counts. (G) Skewing of the BcR IGH repertoire was detectable for CLL requiring treatment (red triangles) and indolent CLL during follow-up (blue circles), with a median follow-up period of 8.7 years. (H) Skewing of the IGH repertoire was detectable for patients with a transformation to an aggressive B-cell lymphoma and those without transformation during follow-up.