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. 2014 Apr;99(4):726-35.
doi: 10.3324/haematol.2013.091827. Epub 2013 Oct 31.

Biological Characterization of Adult MYC-translocation-positive Mature B-cell Lymphomas Other Than Molecular Burkitt Lymphoma

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Free PMC article

Biological Characterization of Adult MYC-translocation-positive Mature B-cell Lymphomas Other Than Molecular Burkitt Lymphoma

Sietse M Aukema et al. Haematologica. .
Free PMC article

Abstract

Chromosomal translocations affecting the MYC oncogene are the biological hallmark of Burkitt lymphomas but also occur in a subset of other mature B-cell lymphomas. If accompanied by a chromosomal break targeting the BCL2 and/or BCL6 oncogene these MYC translocation-positive (MYC(+)) lymphomas are called double-hit lymphomas, otherwise the term single-hit lymphomas is applied. In order to characterize the biological features of these MYC(+) lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation-positive lymphomas (31 single-hit, 46 double-hit and 3 MYC(+)-lymphomas with unknown BCL6 status). Comparison of single-hit and double-hit lymphomas revealed no difference in MYC partner (IG/non-IG), genomic complexity, MYC expression or gene expression profile. Double-hit lymphomas more frequently showed a germinal center B-cell-like gene expression profile and had higher IGH and MYC mutation frequencies. Gene expression profiling revealed 130 differentially expressed genes between BCL6(+)/MYC(+) and BCL2(+)/MYC(+) double-hit lymphomas. BCL2(+)/MYC(+) double-hit lymphomas more frequently showed a germinal center B-like gene expression profile. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In this series of lymphomas, in which immunochemotherapy was administered in only a minority of cases, single-hit and double-hit lymphomas had a similar poor outcome in contrast to the outcome of molecular Burkitt lymphoma and lymphomas without the MYC break. Our data suggest that, after excluding molecular Burkitt lymphoma and pediatric cases, MYC(+) lymphomas are biologically quite homogeneous with single-hit and double-hit lymphomas as well as IG-MYC and non-IG-MYC(+) lymphomas sharing various molecular characteristics.

Figures

Figure 1.
Figure 1.
(A) Genomic complexity as assessed by array-comparative genomic hybridization. There is no significant difference in the number of aberrant segments between DHL and SHL (P=0.255). Both SHL as well as DHL show a significantly higher genomic complexity than IG-MYC mBL (P=0.038 for SHL and P<0.001 for DHL versus IG-MYC mBL). (B) IGH mutational frequency in SHL and DHL. DHL shows a significantly higher mutational frequency (P<0.001). (C) Number of MYC mutations in DHL and SHL. DHL show a significantly higher number of MYC mutations (P=0.048). (D) Expected (X-axis) versus observed (Y-axis) test scores between SHL and DHL. The distribution of the expected scores is estimated by repeatedly computing test scores from the same SHL/DHL data with randomly permutated class labels. Observed scores were computed by genewise analysis taking the log ratios of the SHL and DHL collective. The red lines mark the 95% confidence intervals on the absolute difference between observed and expected scores. Colored dots represent genes whose observed score exceeds the confidence bounds, whereas this does not directly imply differential expression as the false discovery rate is defined to be ≤0.05. The permutation approach is described in detail in Scheid et al. (E) MYC transcript expression. No difference in MYC expression was seen between SHL and DHL (P=0.490). Both grouped together as well as individually, SHL and DHL have higher MYC transcript expression compared with MYC-negative lymphomas (P<0.001) but lower expression than IG-MYC mBL (P<0.01 for SHL and P<0.001 for DHL).
Figure 2.
Figure 2.
(A) Comparison of survival between DHL and SHL shows no significant differences between the two groups (P=0.690). The blue line represents SHL, the red line represents DHL. (B) Comparison of survival between DHL and SHL restricted to lymphomas with a morphological diagnosis of DLBCL (without any follicular lymphoma component). No difference was seen in survival (P=0.586). The blue line represents SHL, the red line represents DHL. (C) Overall survival of patients with MYC+ and MYC lymphomas with non-mBL or Intermediate gene-expression profile in the MMML cohort. Patients with MYC+ lymphomas show markedly inferior survival compared to those with MYC lymphomas (P<0.001). The blue line represents MYC+ lymphomas, the red line represents MYC lymphomas.
Figure 3.
Figure 3.
Biology of BCL2+/MYC+ versus BCL6+/MYC+ DHL. (A) IGH mutational frequency; (B) Number of MYC mutations; (C) Genomic complexity assessed by number of aberrant segments; (D) Comparison of gene expression profiles. One hundred thirty gene tags were differentially expressed between BCL2+/MYC+ and BCL6+/MYC+ DHL. Samples are ordered according to gene expression index calculated as described in the Online Supplementary Materials and Methods with the lowest index at the very left end. BCL2+/MYC+ (gray), BCL6+/MYC+ (purple) and BCL2+/BCL6+/MYC+ (orange). Cell-of-origin labels are added at the very top of the figure (GCB-like, blue; ABC-like, green; unclassified, magenta). (E) MYC transcript expression in BCL2+/MYC+ and BCL6+/MYC+ DHL. BCL6+/MYC+ DHL showed a trend towards higher transcript expression (P=0.130). MYC transcript expression in both BCL2+/MYC+ and BCL6+/MYC+ DHL was higher compared to that in MYC-negative lymphomas (P<0.001).

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