Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas

Area of Science:

• Hematology
• Oncology
• Genomics

Background:

• Molecular mechanisms driving frequent diffuse large B-cell lymphoma (DLBCL) relapse remain unclear.
• The contribution of primary tumor clonal heterogeneity to DLBCL relapse is poorly understood.
• Investigating B-cell lymphoma-specific features like VDJ recombination and somatic hypermutation offers insights into relapse.

Purpose of the Study:

• To elucidate the molecular mechanisms and clonal evolution patterns underlying diffuse large B-cell lymphoma (DLBCL) relapse.
• To explore the role of tumor heterogeneity in DLBCL recurrence.
• To identify potential therapeutic targets for DLBCL relapse based on distinct evolutionary pathways.

Main Methods:

• High-throughput sequencing of rearranged VDJ junctions from 14 matched diagnosis-relapse DLBCL tumor pairs.
• Exome sequencing for detailed mutational analysis in 7 of the matched pairs.
• Phylogenetic analysis of VDJ junction data to infer clonal evolution.

Main Results:

• Identified two distinct modes of DLBCL relapse evolution: early-divergent and late-divergent.
• Early-divergent mode: Clonal divergence occurred early, with parallel evolution of diagnosis and relapse tumors.
• Late-divergent mode: Relapse tumors evolved directly from diagnosis tumors with minimal divergence.
• Mutations in epigenetic modifiers (e.g., KMT2D) implicated as early drivers; immune escape alterations linked to relapse.

Conclusions:

• DLBCL relapse arises from multiple, distinct tumor evolutionary mechanisms, necessitating mechanism-specific therapies.
• Highlights the urgent need to understand the role of epigenetic modifier mutations in lymphomagenesis.
• Emphasizes the importance of investigating genetic lesions in immune surveillance factors in DLBCL relapse.