Helen Parker, Amatta Mirandari, Ben Stevens, Carolina Jaramillo-Oquendo, Martí Duran-Ferrer, Lara Buermann, Harindra E. Amarasinghe, Jaya Thomas, Louise Carr, Shama Syeda, Methusha Sakthipakan, Marina Parry, M Rose-Zerilli, Zadie Davis, Neil R. McIver-Brown, Aliki Xochelli, Sarah Ennis, Lydia Scarfò, P Ghia, Christina Kalpadakis, Gerassimos A. Pangalis, Davide Rossi, Gianluca Gaidano, Simon D. Wagner, Matthew J. Ahearne, Marc Seifert, Christoph Plass, Dieter Weichenhan, Eva Kimby, Lesley-Ann Sutton, R. Rosenquist, Rose‐Marie Amini, Viktor Ljungström, Guy Pratt, Francesco Forconi, Kostas Stamatopoulos, Marta Salido, Ana Ferrer, C Thieblemont, Laura K. Hilton, Ryan D. Morin, Renata Walewska, Jose Ignacio Martin-Subero, David Graham Oscier, Christopher C. Oakes, Jane Gibson, Dean Bryant, Jonathan C. Strefford
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 patients with SMZL-HR required treatment and showed a higher frequency of transformation (P = .007) and mortality (P< .001). Multivariate analysis confirmed SMZL-HR as an independent predictor of shorter TTFT (hazard ratio, 2.4; P = .001). These findings demonstrate the role of DNA methylation and molecular profiling in SMZL risk stratification.