Integrated multiomic profiling reveals 2 distinct splenic marginal zone lymphoma subgroups with prognostic relevance

作者：Helen Parker, Amatta Mirandari, Ben Stevens, Carolina Jaramillo-Oquendo, Martí Duran‐Ferrer, Lara E. Buermann, Harindra Eranthi Amarasinghe, Jaya Thomas, Louise J. Carr, Shama Syeda, Methusha Sakthipakan, Marina Parry, Matthew J.J. Rose-Zerilli, Zadie A. Davis, Neil McIver‐Brown, Aliki Xochelli, Sarah A. Ennis, Lydia Scarfò, Paolo Ghia, Christina Kalpadakis, Gerassimos A. Pangalis, Davide Rossi, Gianluca Gaïdano, Simon D. Wagner, Matthew J. Ahearne, Marc Seifert, Christoph Plass, Dieter Weichenhan, Eva K. Kimby, Lesley-Ann Sutton, Richard Rosenquist, Rose‐Marie Amini, Viktor Ljungström, Guy Pratt, Francesco Forconi, Kostas Stamatopoulos, Marta Salido, Ana Ferrer, Catherine Thiéblemont, Laura K. Hilton, Ryan D. Morin, Renata J. Walewska, José Ignacio Martín-Subero, David Graham Oscier, Christopher C. Oakes, Jane Gibson, Dean Bryant, Jonathan C. Strefford · 发表于：Blood Advances · 年份：2026 · DOI：10.1182/bloodadvances.2025019336 · 被引用次数：2 · 研究领域：Lymphoma Diagnosis and Treatment、Multiple and Secondary Primary Cancers、CNS Lymphoma Diagnosis and Treatment

ABSTRACT: Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy with notable genetic, epigenetic, and clinical heterogeneity. In this study, we used coding and noncoding sequencing (n = 74), including whole-genome sequencing (WGS) of 24 paired tumor-normal samples, targeted sequencing (n = 55), and DNA methylation in 126 patients to characterize the disease. From WGS, we identified recurrent, predominantly clonal coding mutations in KLF2 (50%), KMT2D (25%), and NOTCH2 (25%), alongside rare mutations in FLNC (8%), novel mutations in FAM135B (17%), and noncoding mutational hot spots in BCL6, PAX5, and BACH2 linked to aberrant somatic hypermutation. At least 1 noncoding hot spot was detected in 69% of patients. Copy number aberrations were present in 73% of patients, including del(7q) (27%), gain(3q) (17%), and trisomy 12 (13%). DNA methylation profiling revealed 2 epigenetic subgroups: high-risk (HR) SMZL (n = 67) and low-risk SMZL (n = 59). SMZL-HR was associated with adverse features, including female sex, IGHV1-2∗04 usage, KLF2 mutations, del(7q), shorter telomeres, and elevated epigenetically determined cumulative mitoses scores. Transcriptomic analysis highlighted enhanced cell proliferation in SMZL-HR, with enrichment of E2F and G2M checkpoint pathways and epigenetic regulation via EZH2. Patients with SMZL-HR had significantly shorter time to first treatment (TTFT) (hazard ratio, 1.9; P = .003) and reduced overall survival (hazard ratio, 2.5; P = .039): 85% of...