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

Area of Science:

• Hematology
• Oncology
• Genetics

Background:

• Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy characterized by significant heterogeneity.
• Understanding the molecular underpinnings of SMZL is crucial for improved diagnosis and treatment.

Purpose of the Study:

• To comprehensively characterize the genetic and epigenetic landscape of SMZL.
• To identify molecular features associated with disease risk and clinical outcomes.
• To establish a molecular basis for risk stratification in SMZL patients.

Main Methods:

• Whole-genome sequencing (WGS), targeted sequencing, and DNA methylation profiling were performed on a cohort of 126 SMZL cases.
• Copy-number aberration (CNA) analysis and transcriptomic profiling were also conducted.
• Statistical analyses, including multivariate analysis, were used to correlate molecular findings with clinical data.

Main Results:

• Recurrent coding mutations were identified in KLF2, KMT2D, and NOTCH2. Non-coding mutational hotspots in BCL6, PAX5, and BACH2 were linked to aberrant somatic hypermutation.
• DNA methylation profiling delineated two distinct epigenetic subgroups: SMZL-HR (high-risk) and SMZL-LR (low-risk).
• SMZL-HR was associated with adverse clinical features, shorter time to first treatment (TTFT), and reduced overall survival, and was an independent predictor of shorter TTFT.

Conclusions:

• Molecular profiling, particularly DNA methylation, plays a critical role in stratifying SMZL patients by risk.
• Identification of SMZL-HR as a high-risk subgroup provides valuable prognostic information.
• These findings pave the way for more personalized treatment strategies in SMZL.