Journal Article

DKFZ-2026-01279

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Integrated multi-omic profiling reveals two distinct splenic marginal zone lymphoma subgroups with prognostic relevance.

Parker, H. ; Mirandari, A. ; Stevens, B. ; Jaramillo-Oquendo, C. ; Duran-Ferrer, M. ; Buermann, L. ; Amarasinghe, H. E. ; Thomas, J. ; Carr, L. ; Syeda, S. ; Sakthipakan, M. ; Parry, M. ; Rose-Zerilli, M. J. ; Davis, Z. A. ; McIver-Brown, N. R. ; Xochelli, A. ; Ennis, S. ; Scarfò, L. ; Ghia, P. ; Kalpadakis, C. ; Pangalis, G. A. ; Rossi, D. ; Gaidano, G. ; Wagner, S. D. ; Ahearne, M. J. ; Seifert, M. ; Plass, C.DKFZ* ; Weichenhan, D.DKFZ* ; Kimby, E. K. ; Sutton, L.-A. ; Rosenquist, R. ; Amini, R.-M. ; Ljungström, V. ; Pratt, G. ; Forconi, F. ; Stamatopoulos, K. ; Salido, M. ; Ferrer, A. ; Thieblemont, C. ; Hilton, L. K. ; Morin, R. D. ; Walewska, R. ; Martin-Subero, J. I. ; Oscier, D. G. ; Oakes, C. C. ; Gibson, J. ; Bryant, D. ; Strefford, J. C.

2026
American Society of Hematology Washington, DC

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.

Note: epub

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Contributing Institute(s):

1. Epigenomik (B370)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2026

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