IG-MYC+ neoplasms with precursor B-cell phenotype are molecularly distinct from Burkitt lymphomas

Abstract

The "WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue" notes instances of Burkitt lymphoma/leukemia (BL) with IG-MYC-rearrangement displaying a B-cell precursor immunophenotype (termed herein "preBLL"). To characterize the molecular pathogenesis of preBLL we investigated 13 preBLL cases (including one cell line) of which 12 were analyzable using genome, exome, and targeted sequencing, imbalance mapping, and DNA-methylation profiling. In five patients with reads across the IG-MYC breakpoint junctions we found evidence that the translocation derived from an aberrant VDJ-recombination, as typical for IG translocations arising in B-cell precursors. Genomic changes like bi-allelic IGH-translocations or VDJ-rearrangements combined with translocation into the VDJ-region on the second allele potentially preventing expression of a productive immunoglobulin were detected in 6/13 cases. We did not detect mutations in genes frequently altered in BL, but instead activating NRAS and/or KRAS mutations in 7/12 preBLL. Gains on 1q, recurrent in BL and preB-lymphoblastic leukemia/lymphoma (pB-ALL/LBL), were detected in 7/12 preBLL. DNA-methylation profiling showed the preBLL to cluster with precursor B-cells and pB-ALL/LBL but apart from BL. We conclude that preBLL genetically and epigenetically resemble pB-ALL/LBL rather than BL. Thus, we propose that BL with B-cell precursor phenotype should be considered as a pB-ALL/LBL with recurrent genetic abnormalities.