Depending on disease stage follicular lymphoma (FL) lack the t(14;18) in ~15–~50% of cases. Nevertheless, most of these cases express BCL2. To elucidate mechanisms triggering BCL2 expression and promoting pathogenesis in t(14;18)-negative FL, exonic single-nucleotide variant (SNV) profiles of 28 t(14;18)-positive and 13 t(14;18)-negative FL were analyzed, followed by the integration of copy-number changes, copy-neutral LOH and published gene-expression data as well as the assessment of immunoglobulin N-glycosylation sites. Typical FL mutations also affected t(14;18)-negative FL. Curated gene set/pathway annotation of genes mutated in either t(14;18)-positive or t(14;18)-negative FL revealed a strong enrichment of same or similar gene sets but also a more prominent or exclusive enrichment of immune response and N-glycosylation signatures in t(14;18)-negative FL. Mutated genes showed high BCL2 association in both subgroups. Among the genes mutated in t(14;18)-negative FL 555 were affected by copy-number alterations and/or copy-neutral LOH and 96 were differently expressed between t(14;18)-positive and t(14;18)-negative FL (P<0.01). N-glycosylation sites were detected considerably less frequently in t(14;18)-negative FL. These results suggest a diverse portfolio of genetic alterations that may induce or regulate BCL2 expression or promote pathogenesis of t(14;18)-negative FL as well as a less specific but increased crosstalk with the microenvironment that may compensate for the lack of N-glycosylation.
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AZ was supported by the Alexander von Humboldt Stiftung and GO and HH by the Robert-Bosch-Stiftung. This work was supported in part by the German Ministry for Education and Science (BMBF (ICGC MMML-Seq (01KU1002A-J) and ICGC DE-mining (01KU1505G) consortia)).
The authors declare no conflict of interest.
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Zamò, A., Pischimarov, J., Schlesner, M. et al. Differences between BCL2-break positive and negative follicular lymphoma unraveled by whole-exome sequencing. Leukemia 32, 685–693 (2018) doi:10.1038/leu.2017.270
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