Follicular lymphoma subgroups with and without t(14;18) differ in their N-glycosylation pattern and IGHV usage.

We previously reported that t(14;18)-negative follicular lymphomas (FL) show a clear reduction of newly acquired N-glycosylation sites (NANGS) in immunoglobulin genes. We therefore aimed to investigate in-depth the occurrence of NANGS in a larger cohort of t(14;18)-positive and t(14;18)-negative FL, including early (I/II) and advanced (III/IV) stage treatment naive and relapsed tumors. We determined the clonotype using a next generation sequencing approach in a series of 68 FL with fresh frozen material (36 t(14;18)-positive and 32 t(14;18)-negative). The frequency of NANGS differed considerably between t(14;18)-positive and t(14;18)-negative FL III/IV, but no difference was observed among t(14;18)-positive and t(14;18)-negative FL I/II. The introduction of NANGS in all t(14;18)-negative clinical subgroups occurred significantly more often in the FR3 region. Moreover, t(14;18)-negative treatment naive FL, specifically those with NANGS, showed a strong bias for IGHV4-34 usage compared to t(14;18)-positive treatment naive cases with NANGS, while IGHV4-34 usage was never found in relapsed FL. In conclusion, subgroups of t(14;18)-negative FL might use different mechanisms of BCR stimulation compared to the lectin-mediated binding described in t(14;18)-positive FL, including responsiveness to autoantigens as indicated by biased IGHV4-34 usage and strong NANGS enrichment in FR3.