Genetic analysis and clinical correlations in marginal zone lymphoma

Abstract Background: Marginal zone lymphoma (MZL) is a heterogeneous group of indolent B-cell malignancies with distinct molecular landscapes across its subtypes (extranodal/MALT, splenic, nodal, and disseminate). Genetic characteristics of MZL and its clinical relevance were not well defined. This study aims to explore subtype-specific genetic signatures and their clinical correlations in a retro-prospective MZL cohort Methods: We retrospectively analyzed MZL patients who underwent targeted Next-Generation Sequencing(NGS) panel for lymphoproliferative disorders at our institution and examining their mutational profiles and correlations with clinical characteristics and outcomes. Results:From December 2017 and August 2024, 136 MZL patients with NGS testing results underwent systemic treatment in our center. The median age was 63 years (range 30–92) and the male-to-female ratio was 1.1. This cohort comprised 52(38.2%) MALT/EMZL, 7(5.2%) NMZL, 65 (47.8%)SMZL and 12(8.8%) dissMZL patients, respectively. The most frequently detected mutations were MYD88L265P(13.2%),TP53 (12.5%), CXCR4 (6.6%), DNMT3A (6.6%), EP300 (6.6%), TET2 (5.9%),TNFAIP3 (5.1%)，in descending order of frequency. No associations were found between mutations and clinical features such as Ann Arbor stage or MZL-IPI. However, patients with large B cell transformation showed higher frequencies of EP300 (22.2% vs. 4.3%, p=0.019) and EZH2 (11.1% vs. 0.1%, p=0.017) mutations. TNFAIP3 mutations varied significantly across subtypes: 0% (MALT/EMZL), 14.3% (NMZL), 9.2% (SMZL), and 0% (dissMZL) (p=0.045). With median follow-up of 65.3months(range 2.2-262), the 5-year PFS and OS rates were 46.1% (95% CI 36.8–57.5) and 85.2% (78.5–92.4), respectively. Progression of disease within 24 months was observed in 27.4% of patients. TP53 mutations adversely impacted OS (HR 2.85, 95% CI 1.17–6.95; p=0.014) but not PFS. No other mutations predicted survival. Conclusion: This study delineates the distinct mutational landscape of MZL, revealing subtype-specific patterns (TNFAIP3 variation) and transformation-associated alterations (EP300/EZH2). The adverse impact of TP53 mutations on OS underscores its prognostic value, while the 27.4% POD24 rate highlights unmet needs in high-risk subsets. These findings advocate for integrating molecular profiling (particularly TP53, EP300, and TNFAIP3) with clinical indices like MZL-IPI to refine risk stratification and guide targeted therapy development in MZL.