Integrated analysis of IGHV rearrangements and cytogenetic abnormalities in a large chronic lymphocytic leukemia cohort (CLL-POL1).

The somatic hypermutation (SHM) status of immunoglobulin heavy-chain variable region gene (IGHV) is a well-established prognostic factor in chronic lymphocytic leukemia (CLL). We analyzed clonotypic IGHV-IGHD-IGHJ rearrangements in 4,251 newly diagnosed CLL patients in Poland (CLL-POL1), representing the largest national cohort to date. In total, 4,328 productive rearrangements were evaluated, of which 93% represented single clonal rearrangements. Additionally, double productive clonal rearrangements were identified in 76 cases (1.8%), of which 27 (35.5%) displayed discordant IGHV SHM status. Stereotyped B-cell receptor subsets were assigned to 10.6% of sequences, predominantly enriched in unmutated CLL (U-CLL) compared to mutated CLL (M-CLL) (72.8% vs. 22%; p < 0.001). High-risk subsets (#1, #2, #5, #6, #59, #99) accounted for over a half of all stereotyped cases and were enriched in patients with TP53 mutation. Most stereotyped subsets showed preferential or exclusive usage of specific IGHV genes. Integration of cytogenetic data revealed a strong enrichment of del(17p), del(11q), and trisomy 12 within U-CLL, whereas M-CLL was characterized by higher frequency of isolated del(13q). In summary, this study highlights distinct IGHV-IGHD-IGHJ pairing preferences and the heterogenous distribution of stereotyped subsets, revealing biologically meaningful associations with TP53 mutation and cytogenetic profiles.