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

Abstract

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 high-level 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 of genes in 11q.

Figure 1

Diagram of the strategy used for the identification of potential MYC-negative BL. One case from cohort 2 is also part of cohort 3 (MMML series). *mBL and BL-PAP GEP classifiers. ^†Previously published cases.^,

Figure 2

Supervised analysis comparing MYC expression between IG-MYC–positive and MYC-negative lymphomas from mBL and BL-PAP groups. mBL: BL cases defined by mBL index (green); BL-PAP: BL cases defined by BL-PAP index (red); double: BL cases defined by both mBL and BL-PAP indices (black) (P = .014).

Figure 3

Morphologic features of MYC-negative high-grade lymphomas. (A) Hematoxylin and eosin preparation showing the morphology and CD20, CD10, BCL2, and Ki67 expression by immunohistochemistry of (A) case 1, (B) case 2, and (C) case 3 in cohort 2. (D) Heatmap showing the morphologic and the immunohistochemical features of the 17 MYC-negative high-grade lymphomas. The morphologic characteristics included information of the cytology, growth pattern, and bystander cells. Red, pro-Burkitt: medium cell size; no cell polymorphism; narrow cytoplasm; round nuclear shape; multiple, small, and paracentric nucleoli; “starry-sky” growth pattern; scattered bystander cells; and sparse eosinophils. Blue, no BL-like: large cell size; cell polymorphism; abundant cytoplasm; irregular nuclear shape; multiple, small, eccentric (centroblast-like) nucleoli/single, large, central (immunoblast-like) nucleolus/finely, granular (lymphoblast-like)/other chromatin; absent “starry-sky” growth pattern; abundant bystander cells. Immunohistochemical analyses included data on CD20, CD10, CD5, BCL2, BCL6, and Ki67. –, negative; +, positive; IHC, immunohistochemistry; na, not available; P, partial.

Figure 4

11q alterations in MYC-negative high-grade lymphomas. (A) Chromosomal view of chromosome 11 analyzed by SNP arrays in cohort 2 (n = 14, including SU-DHL-5 and HT cell lines). (B) Chromosomal view of chromosome 11 analyzed by custom CGH-array in cohort 3 (n = 6).