Title : Diagnostic and therapeutic significance of EZH2 and STAT6 mutations detected by targeted deep sequencing of plasma cfDNA with implications on personalized medicine

Follicular lymphoma (FL) is the second most frequent non-Hodgkin lymphoma and is characterized by clinical and genetic heterogeneity. The clinical course of FL varies widely, ranging from asymptomatic cases to those that transform into aggressive B-cell lymphomas. As with other non-Hodgkin lymphomas, precision oncology approaches are essential to improve diagnostic accuracy and identify novel therapeutic targets. Although the genomic landscape of FL has been largely elucidated through next-generation sequencing, these genetic alterations offer potential not only for enhancing diagnosis and prognosis but also for enabling noninvasive genomic profiling via plasma cell-free DNA (cfDNA). Utilizing targeted ultra-deep sequencing of plasma cfDNA and tumor tissue DNA, we evaluated 110 FL-related genes and identified STAT6 and EZH2 as frequently mutated. To isolate variants strictly associated with hematological malignancies, we applied a computational bioinformatics pipeline with stringent filtering. STAT6 and EZH2 mutations were detected in 25% and 20% of FL cases, respectively. STAT6 mutations were enriched within the STAT-binding domain, whereas mutations in EZH2 primarily clustered within the SET domain. Notably, 15% of STAT6 and 10% of EZH2 mutations identified in tumor tissues were also detectable in matching plasma cfDNA samples. In conclusion, these findings underscore the potential of non-invasive diagnostic approaches and highlight therapeutic strategies targeting the EZH2 and/or JAK-STAT6 pathways in mutation-positive FL cases. However, potential limitations regarding drug efficacy and safety profiles must be carefully considered.

Assoc. Prof. Dr. Can Küçük completed his Ph.D. studies on oncology and cancer biology at the University of Nebraska Medical Center (UNMC). He performed post-doctoral studies at UNMC and City of Hope Medical Center. Dr. Küçük has publications in high impact journals such as Nature Communications, Blood, or PNAS. He earned prestigious international awards from the American Society of Hematology and the National Natural Science Foundation of China. Dr. Küçük’s research focuses on genomic, transcriptomic, and epigenomic aberrations causing lymphoid cancers to identify biomarkers that can improve diagnosis or prognostication of lymphoid cancers and to discover more effective therapeutic targets.