Integrated multi-omic profiling reveals two distinct splenic marginal zone lymphoma subgroups with prognostic relevance

Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy with notable genetic, epigenetic, and clinical heterogeneity. This study utilized coding and non-coding sequencing (n=74), including whole-genome sequencing (WGS) on 24 paired tumour-normal samples, targeted sequencing (n=55) and DNA methylation in 126 cases 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 non-coding mutational hotspots in BCL6, PAX5 and BACH2, linked to aberrant somatic hypermutation. At least one non-coding hotspot was detected in 69% of cases. Copy-number aberrations (CNAs) were present in 73% of cases, including del(7q) (27%), gain(3q) (17%) and trisomy 12 (13%). DNA methylation profiling revealed two epigenetic subgroups: SMZL-HR (high-risk, n=67) and SMZL-LR (low-risk, n=59). SMZL-HR was associated with adverse features such as female sex, IGHV1-2*04 usage, KLF2 mutations, del(7q), shorter telomeres, and elevated epiCMIT scores. Transcriptomic analysis highlighted enhanced cell proliferation in SMZL-HR, with enrichment of E2F and G2M checkpoint pathways and epigenetic regulation via EZH2. SMZL-HR patients had significantly shorter time to first treatment (TTFT) (HR: 1.9, p=.003) and reduced overall survival (HR: 2.5, p=.039): 85% of SMZL-HR patients 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 (HR: 2.4, p=.001). These findings demonstrate the role of DNA methylation and molecular profiling in SMZL risk stratification.

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Journal
Blood Advances
Published
2026-05-27
DOI
https://doi.org/10.1182/bloodadvances.2025019336
Primary Topic
Lymphoma Diagnosis and Treatment
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article
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article

Integrated multi-omic profiling reveals two distinct splenic marginal zone lymphoma subgroups with prognostic relevance

Laura K. Hilton, Aliki Xochelli, Christoph Plass, M Rose-Zerilli et al.
Blood Advances
Lymphoma Diagnosis and Treatment
article

Integrated multi-omic profiling reveals two distinct splenic marginal zone lymphoma subgroups with prognostic relevance

Laura K. Hilton, Aliki Xochelli, Christoph Plass, M Rose-Zerilli, Ana Ferrer, Matthew J. Ahearne, Harindra E. Amarasinghe, Rose‐Marie Amini, Amatta Mirandari, R. Rosenquist, Christopher C. Oakes, Jonathan C. Strefford, Viktor Ljungström, Zadie Davis, P Ghia, Helen Parker, Eva Kimby, Simon D. Wagner, Gerassimos A. Pangalis, Francesco Forconi, Jaya Thomas, Methusha Sakthipakan, Carolina Jaramillo-Oquendo, Ben Stevens, Dieter Weichenhan, Davide Rossi, Guy Pratt, C Thieblemont, Ryan D. Morin, Christina Kalpadakis, Martí Duran-Ferrer, Dean Bryant, Renata Walewska, David Graham Oscier, Kostas Stamatopoulos, Neil R. McIver-Brown, Sarah Ennis, Jose Ignacio Martin-Subero, Marc Seifert, Marina Parry, Gianluca Gaidano, Lesley-Ann Sutton, Lara Buermann, Jane Gibson, Shama Syeda, Lydia Scarfò, Marta Salido, Louise Carr
article en

Abstract

Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy with notable genetic, epigenetic, and clinical heterogeneity. This study utilized coding and non-coding sequencing (n=74), including whole-genome sequencing (WGS) on 24 paired tumour-normal samples, targeted sequencing (n=55) and DNA methylation in 126 cases 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 non-coding mutational hotspots in BCL6, PAX5 and BACH2, linked to aberrant somatic hypermutation. At least one non-coding hotspot was detected in 69% of cases. Copy-number aberrations (CNAs) were present in 73% of cases, including del(7q) (27%), gain(3q) (17%) and trisomy 12 (13%). DNA methylation profiling revealed two epigenetic subgroups: SMZL-HR (high-risk, n=67) and SMZL-LR (low-risk, n=59). SMZL-HR was associated with adverse features such as female sex, IGHV1-2*04 usage, KLF2 mutations, del(7q), shorter telomeres, and elevated epiCMIT scores. Transcriptomic analysis highlighted enhanced cell proliferation in SMZL-HR, with enrichment of E2F and G2M checkpoint pathways and epigenetic regulation via EZH2. SMZL-HR patients had significantly shorter time to first treatment (TTFT) (HR: 1.9, p=.003) and reduced overall survival (HR: 2.5, p=.039): 85% of SMZL-HR patients 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 (HR: 2.4, p=.001). These findings demonstrate the role of DNA methylation and molecular profiling in SMZL risk stratification.

Blood Advances
Università degli Studi del Piemonte Orientale “Amedeo Avogadro” (IT), Uppsala University (SE), University of Leicester (GB), Vita-Salute San Raffaele University (IT), German Cancer Research Center (DE), Simon Fraser University (CA), Heidelberg University (DE), Royal Bournemouth Hospital (GB), Karolinska Institutet (SE), University College Birmingham (GB), University of Oxford (GB), Düsseldorf University Hospital (DE), Information Technologies Institute (GR), Assistance Publique – Hôpitaux de Paris (FR), Institute of Oncology Research (CH), Hospital Del Mar (ES), Athens Medical Center (GR), Centre for Research and Technology Hellas (GR), University Hospital of Heraklion (GR), Hôpital Saint-Louis (FR), Bioinformatics Institute (SG), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), University of Southampton (GB), Heinrich Heine University Düsseldorf (DE), University College London (GB), The Ohio State University (US), University of Birmingham (GB)
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Openalex Percentile: Top 8%
Lymphoma Diagnosis and Treatment
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