Definition of MYC genetic heteroclonality in diffuse large B-cell lymphoma with 8q24 rearrangement and its impact on protein expression

Abstract

MYC rearrangement can be detected in a subgroup of diffuse large B-cell lymphoma characterized by unfavorable prognosis. In contrast to Burkitt lymphoma, the correlation between MYC rearrangement and MYC protein expression in diffuse large B-cell lymphoma is less clear, as approximately one-third of rearranged cases show negative or low expression by immunohistochemistry. To better understand whether specific characteristics of the MYC rearrangement may influence its protein expression, we investigated 43 de novo diffuse large B-cell lymphoma positive for 8q24 rearrangement by FISH, using 14 Burkitt lymphoma for comparison. Different cell populations (clones), breakpoints (classical vs non-classical FISH patterns), partner genes (IGH vs non-IGH) and immunostaining were detected and analyzed using computerized image systems. In a subgroup of diffuse large B-cell lymphoma, we observed different clones within the same tumor distinguishing the founder clone with MYC rearrangement alone from other subclones, carrying MYC rearrangement coupled with loss/extra copies of derivatives/normal alleles. This picture, which we defined MYC genetic heteroclonality, was found in 42% of cases and correlated to negative MYC expression (P = 0.026). Non-classical FISH breakpoints were detected in 16% of diffuse large B-cell lymphoma without affecting expression (P = 0.040). Non-IGH gene was the preferential partner of rearrangement in those diffuse large B-cell lymphoma showing MYC heteroclonality (P = 0.016) and/or non-classical FISH breakpoints (P = 0.058). MYC heteroclonality was not observed in Burkitt lymphoma and all cases had positive MYC expression. Non-classical FISH MYC breakpoint and non-IGH partner were found in 29 and 20% of Burkitt lymphoma, respectively. In conclusion, MYC genetic heteroclonality is a frequent event in diffuse large B-cell lymphoma and may have a relevant role in modulating MYC expression. Diffuse large B-cell lymphoma is the most common mature aggressive B-cell lymphoma. Despite recent therapeutic achievements, approximately 40% of diffuse large B-cell lymphoma cannot be cured, which indicates the need for further studies focusing on the characterization of the putative genes involved in diffuse large B-cell lymphoma pathogenesis. In this context, MYC has a relevant role, and the presence of MYC rearrangement, described in approximately 5 to 15% of diffuse large B-cell lymphoma cases, correlates with worse prognosis and poor response to R-CHOP treatment. [1][2][3][4][5] A novel commercial monoclonal antibody has improved the detection of MYC protein expression by immunohistochemistry in formalin-fixed paraffin-embedded tissues. Using this antibody, Burkitt

IgA-producing lymphoplasmacytic lymphoma carrying the chromosomal abnormality t(8;14)

“…Therefore, we performed immunostaining for c-myc using the biopsied lymph node, which was negative, suggesting a different role for c-myc in lymphoma growth in the present patient because this oncogene potently promotes neoplastic growth in Burkitt lymphoma 5 or double-hit/double expressor diffuse large B-cell type malignant lymphoma (DLBCL) 9 , 10 . In DLBCL, c-myc immunostaining becomes positive when c-myc is solely rearranged and involved in tumorigenesis, but it becomes negative when the c-myc rearrangement is secondary to clonal evolution of pre-existing chromosomal abnormalities 11 . In this situation, the t(8;14)(q24;q32) observed in the present patient may have been an additional chromosomal abnormality.…”

Anti-myelocytomatosis tag antibody detects myelocytomatosis oncogene expression in Burkitt lymphoma

“…5 A study by Valera et al demonstrated multiple genetic pathways that culminate in MYC overexpression in B-cell lymphomas, including the loss and gain of copies. 23 The IHC staining performance of antibodies may be affected by factors such as type of fixation, fixation time, time in storage and the storage conditions, which may be true for 9E10.…”

DecreasedCD11c‐positive dendritic cells in the tumor microenvironment predict double‐hit/triple‐hit genotype and survival in diffuse large B‐cell lymphoma

“…Rearrangement was defined by the presence of adequate cells with split signals, which was defined as a green signal that was two signal diameters away from a red signal or vice versa. Cells with independent green signals with no red signal nearby, or vice versa, were also considered positive for split signals [ 17 ]. We used non‐neoplastic tonsil from 20 control individuals to determine the cut‐off values, which were defined to be three standard deviations from the mean.…”