Genomic Architecture of IRF4 Rearrangements in Children and Adult Large B-cell Lymphomas

Area of Science:

• Hematology and Oncology
• Genetics and Genomics
• Molecular Pathology

Background:

• Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) predominantly affects children and young adults (CAYA), presenting with localized disease and excellent prognosis.
• The role of cryptic rearrangements and the biological entity of IRF4-rearranged LBCL (IRF4-R LBCL) in adults remain unclear.
• Understanding age-related differences in IRF4-R LBCL is crucial for accurate classification and treatment.

Purpose of the Study:

• To investigate the molecular and genetic differences between LBCL-IRF4 in CAYA and adult patients.
• To determine if adult IRF4-R LBCL represents the same biological entity as the pediatric/young adult form.
• To identify distinct genetic features and mutational profiles associated with age in IRF4-R LBCL.

Main Methods:

• Integrative molecular analysis of 35 CAYA and 7 adult LBCL-IRF4 cases.
• Targeted sequencing for structural variant analysis (SV-NGS) to confirm IRF4 rearrangements.
• Whole-exome sequencing to identify mutations and analyze genetic complexity.

Main Results:

• IRF4 rearrangements were confirmed in 84% of cases by SV-NGS.
• CAYA cases showed enrichment of IGH translocations (55%), including cryptic insertions.
• Adult IRF4-R LBCL exhibited higher genetic complexity, distinct mutations (KMT2D, DTX1, MYD88-L265P), and predicted subtypes (EZB, MCD), correlating with extranodal involvement and advanced stage.

Conclusions:

• IRF4-R LBCL in adults possesses distinct genetic architecture and mutational profiles compared to CAYA.
• Age-dependent differences in genetic features suggest that adult IRF4-R LBCL may not be the same biological entity as in CAYA.
• These findings support the need for age-stratified classification of IRF4-R LBCL.