Mutational patterns along different evolution paths of follicular lymphoma

Area of Science:

• Oncology
• Immunology
• Genetics

Background:

• Follicular lymphoma (FL) is an indolent B-cell malignancy with a long median survival but frequent relapses.
• FL can transform into more aggressive diffuse large B-cell lymphoma (t-FL).
• Tumor clonal evolution in FL can follow direct or divergent patterns based on immunoglobulin heavy chain variable (IgHV) gene mutations.

Purpose of the Study:

• To characterize somatic hypermutation (SHM) patterns in IgHV genes of sequential FL samples.
• To compare mutation mechanisms and selection forces between FL, t-FL, and healthy controls.
• To investigate changes associated with FL transformation.

Main Methods:

• Analysis of IgHV gene sequences from sequential FL biopsies.
• Comparison of mutation distribution and lineage tree measurements between tumor and non-tumor clones.
• Assessment of N-glycosylation site accumulation due to SHM.

Main Results:

• FL and t-FL tumor clones showed similar IgHV mutation distributions.
• Lower initial clone affinity or selection thresholds were observed in FL compared to controls, but not between FL and t-FL.
• Both FL and t-FL clones accumulated more N-glycosylation sites via SHM.

Conclusions:

• FL transformation to t-FL does not appear to involve significant alterations in DNA targeting or repair mechanisms.
• Selection thresholds remain similar during the progression from FL to t-FL.
• Somatic hypermutation patterns and their consequences, like N-glycosylation site accumulation, are comparable between FL and t-FL.