A recurrent 11q aberration pattern characterizes a subset of MYC-negative high-grade B-cell lymphomas resembling Burkitt lymphoma

Abstract

Key Points• A subset of lymphomas with gene expression and pathological characteristics of Burkitt lymphomas but absence of MYC translocation does exist.• These lymphomas carry chr 11q proximal gains and telomeric losses, suggesting co-deregulation of oncogenes and tumor suppressor genes.The genetic hallmark of Burkitt lymphoma (BL) is the t(8;14)(q24;q32) and its variants leading to activation of the MYC oncogene. It is a matter of debate whether true BL without MYC translocation exists. Here, we identified 59 lymphomas concordantly called BL by 2 gene expression classifiers among 753 B-cell lymphomas. Only 2 (3%) of these 59 molecular BL lacked a MYC translocation, which both shared a peculiar pattern of chromosome 11q aberration characterized by interstitial gains including 11q23.2-q23.3 and telomeric losses of 11q24.1-qter. We extended our analysis to 17 MYC-negative high-grade B-cell lymphomas with a similar 11q aberration and showed this aberration to be recurrently associated with morphologic and clinical features of BL. The minimal region of gain was defined by highlevel amplifications in 11q23.3 and associated with overexpression of genes including PAFAH1B2 on a transcriptional and protein level. The recurrent region of loss contained a focal homozygous deletion in 11q24.2-q24.3 including the ETS1 gene, which was shown to be mutated in 4 of 16 investigated cases. These findings indicate the existence of a molecularly distinct subset of B-cell lymphomas reminiscent of BL, which is characterized by deregulation

Post-transplant molecularly defined Burkitt lymphomas are frequently MYC-negative and characterized by the 11q-gain/loss pattern

“…Dysregulated genes in the MLR comprise two candidate tumor suppressor genes, TBRG1 and EI24, and five genes either related to cancer or involved in cancer-related processes, including ETS1, TIRAP, ST14, NCAPD3 and ZNF202. Noteworthy, FLI1, the candidate target gene, 3 was not differentially down-regulated in our cases (Online Supplementary Figure S3). Hierarchical clustering of the studied cases using the set of 11q23/q24 dysregulated genes showed that MYCtranslocation-negative PT-mBL cases cluster together and separately from MYC-translocation-positive PT-/IC-mBL ( Figure 1D).…”

“…3,9 Losses, resulting from different non-reciprocal translocations in cases 5 and 6, constantly targeted the 11q23.3q24.1qter region. Homozygous deletions were not detected.…”

Chromosome 11q23 aberrations activating FOXR1 in B-cell lymphoma

“…1, 2, 3 We describe a novel fusion of FOXR1 forkhead box gene, located at 11q23, with a neighboring gene in B-cell lymphoma.…”

Overview of PAF-Degrading Enzymes

“…This recombination event removes the first noncoding exon and places the remaining five exons under the control of IgH regulatory elements. Salaverria et al recently found that 2% of patients with Burkitt lymphoma lack translocation of the MYC oncogene and share an aberration characterized by interstitial gains including 11q23.2-q23.3 [37]. Furthermore, they showed that PAF-AH I α 2 expression is selectively upregulated in cell lines containing the gain of the aberrant 11q23 locus.…”