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The Genetic Landscape of BCL2 Break Negative Follicular Lymphoma

Background: 15% of high and 50% of low stage FL lack the t(14;18). Nevertheless, most of these cases express BCL2 by so far unknown mechanisms. Principals/Methodology: To find molecular mechanisms, triggering FL-pathogenesis in t(14;18)-negative FL, the exonic SNV-profiles of 33 FL with and 16 FL without t(14;18) were assessed by whole exome-sequencing and external SNV-data integration. The SNV-profile of the whole exome-sequenced FL was correlated with copy number, LOH and gene-expression data. Finally, the N-glycosylation status was assessed (LympTrack assay) in a separate validation cohort. Results: SNVs in FL with and without t(14;18) affected different genes, but accumulated in similar pathways, e.g. apoptosis, epigenetic processes and cell cycle/proliferation. Mutations in genes associated with immune-response were more prominently and those associated with NFkB and N-glycosylation selectively enriched in t(14;18)-negative FL. ~50% of mutated genes showed BCL2-asociation at high confidence in FL with and without t(14;18). Moreover, among the genes mutated in t(14;18)-negative FL 555 (~1/3) were affected by copy number alterations and/or copy-neutral LOH, 125 were differently expressed between FL with and without t(14;18) (p<0.01) and 62 were differentially expressed and affected by copy number alterations and/or copy-neutral LOH. N-glycosylation was strongly reduced in t(14;18)-negative FL as compared to results reported for historical FL cohorts. Conclusion: These results suggest a stronger crosstalk with the microenvironment that may compensate for the lack of N-glycosylation and a diverse portfolio of SNVs that may contribute to the upregulation of BCL2 and FL pathogenesis in t(14;18)-negative FL.

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Dataset ID Description Technology Samples
EGAD00001003509 11
EGAD00010001232 Affymetrix SNP 6.0 1
EGAD00010001233 Affymetrix SNP 6.0 1
EGAD00010001234 Affymetrix SNP 6.0 1
EGAD00010001235 Affymetrix SNP 6.0 1
EGAD00010001236 Affymetrix SNP 6.0 1
EGAD00010001237 Affymetrix SNP 6.0 1
EGAD00010001238 Affymetrix SNP 6.0 1
EGAD00010001239 Affymetrix SNP 6.0 1
EGAD00010001240 Affymetrix SNP 6.0 1
EGAD00010001241 Affymetrix SNP 6.0 1