Genetic Susceptibility And Somatic Mutation Profiles in Chronic Lymphocytic Leukemia: Evidence From Whole Exome Sequencing Study

Chronic lymphocytic leukemia (CLL) is the most common hematologic malignancy in adults, characterized by remarkable biological and clinical heterogeneity and by clonal evolution often driven by acquired — and, in some cases, inherited — genetic factors. The present study aimed to characterize the molecular profile of CLL through a comparative genomic analysis between leukemic and non-leukemic cells, integrating clinical, cytogenetic, and molecular data. A cohort of 51 patients was analyzed using Next-Generation Sequencing (NGS) technologies applied to paired samples of peripheral blood mononuclear cells (PBMCs) and granulocytes, enabling the accurate discrimination of germline and somatic variants. Pathogenic or likely pathogenic variants were identified in approximately half of the patients, distributed across genes involved in DNA damage response, genomic stability, and signal transduction pathways. Germline variants predominantly affected genes involved in DNA repair and telomere maintenance, whereas somatic mutations targeted canonical CLL driver genes, including TP53, ATM, BTK, and SF3B1. Overall, the findings suggest that inherited defects in genomic surveillance mechanisms may predispose to clonal instability, facilitating the accumulation of somatic alterations that influence disease evolution and therapeutic response. The integrated analysis supports a model in which germline predisposition and somatic diversification cooperate in shaping CLL biology, providing a basis for more refined molecular stratification and the development of precision medicine strategies.