Burkitt-like lymphoma with 11q aberration: a germinal center-derived lymphoma genetically unrelated to Burkitt lymphoma

Abstract

Burkitt-like lymphoma with 11q aberration is characterized by pathological features and gene expression profile resembling those of Burkitt lymphoma but lacks the MYC rearrangement and carries an 11q-arm aberration with proximal gains and telomeric losses. Whether this lymphoma is a distinct category or a particular variant of other recognized entities is controversial. To improve the understanding of Burkitt-like lymphoma with 11q aberration we performed an analysis of copy number alterations and targeted sequencing of a large panel of B-cell lymphoma-related genes in 11 cases. Most patients had localized nodal disease and a favorable outcome after therapy. Histologically, they were high grade B-cell lymphoma, not otherwise specified (8 cases), diffuse large B-cell lymphoma (2 cases) and only one was considered as atypical Burkitt lymphoma. All cases had a germinal center B-cell signature and phenotype with frequent LMO2 expression. The patients with Burkitt-like lymphoma with 11q aberration had frequent gains of 12q12-q21.1 and losses of 6q12.1-q21, and lacked common Burkitt lymphoma or diffuse large B-cell lymphoma alterations. Potential driver mutations were found in 27 genes, particularly involving BTG2, DDX3X, ETS1, EP300, and GNA13 However, ID3, TCF3, or CCND3 mutations were absent in all cases. These results suggest that Burkitt-like lymphoma with 11q aberration is a germinal center-derived lymphoma closer to high-grade B-cell lymphoma or diffuse large B-cell lymphoma than to Burkitt lymphoma.

Figure 1.

Morphological features of cases of Burkitt-like lymphoma with 11q aberration. (A1-A3) Case #2 shows the typical morphology of diffuse large B-cell lymphomas with large and irregular cells resembling centroblasts. This case was positive for (A2) LMO2 and negative for (A3) MYC. (B1-B3) Case #4 corresponds to a tumor with high-grade B-cell lymphoma (HGBCL) morphology. It is composed mostly of medium-sized cells with mild heterogeneity. Note the “starry sky” pattern. This case was positive for (B2) MYC and (B3) LMO2 expression. (C1-C2; case #7) Lymph node with nodular architecture and a “starry sky” pattern with large follicles and a disrupted follicular cell meshwork highlighted with (C2) CD21. (D1-D2; case #5) This is a case with HGBCL features with expression of (D2) BCL2 in the neoplastic cells.

Figure 2.

Genetic features of cases of Burkitt-like lymphoma with 11q aberration. (A) Global copy number profile of the 11 cases of Burkitt-like lymphoma (BLL) with 11q aberration. The horizontal axis indicates chromosomes from 1 to Y and p to q. The vertical axis indicates the frequency of the genomic aberration among the cases analyzed. Gains are depicted in blue, losses are depicted in red. (B) Individual copy number profile of case #16 showing a prototypical, gain, loss and amplification in the 11q region. Each probe is aligned from chromosome 1 to Y and p to q arm. (C) Mutational overview of ten cases of BLL with 11q aberration. The heat map shows the case-specific pattern of driver mutations found by next-generation sequencing. Each column represents a case and each row represents a gene. The right bar graph illustrates the mutation frequency of each gene. (D) A diagram of the relative positions of driver mutations is shown for BTG2, ETS1 and GNA13 genes. Domains BTG2: BTG family domain. Domains ETS1: PNT: pointed domain; TAD: transactivation domain; H-1/2: inhibitory a-helices 1/2; DBD: DNA binding domain; H4-5: a-helix 4/5. Domains GNA13: G-alpha: G protein a subunit. Circles indicate missense mutations, triangles indicate truncating mutations and rhombi indicate splicing mutations.