Increased MYC gene copy number correlates with increased mRNA levels in diffuse large B-cell lymphoma

Abstract

BackgroundTranslocations involving the MYC gene and increased MYC mRNA levels are associated with poor outcome in diffuse large B-cell lymphoma. However, the presence of increased MYC gene copy number and/or polysomy of chromosome 8 have not been previously described. Design and MethodsUtilizing dual color chromogenic in situ hybridization, we investigated MYC gene copy and chromosome 8 centromere numbers in 52 cases of diffuse large B-cell lymphoma. Cases were divided into those with "increased" or "not increased" MYC gene copy number for comparison with MYC mRNA levels, Ki-67 values, and survival. ResultsIncreased MYC gene copy number was present in 38% of cases. Overall, the average MYC mRNA level was 2398 (range, 342 -9783) and the percentage of nuclei positive for Ki-67 was 57.5% (range, 20-87%). Within the group with increased MYC copy number, the MYC mRNA values ranged from 816 to 5912 (average, 2843) and the Ki-67 values ranged from 23% to 83% (average, 57%). Within the group with not increased MYC copy number, MYC mRNA values ranged from 342 to 9783 (average, 2118) and the Ki-67 values ranged from 20% to 87% (average, 58%). There was a statistically significant relationship between increased MYC gene copy number and increased MYC mRNA (P=0.034) and a trend toward a relationship between increased mRNA and higher Ki-67 values. ConclusionsThis is the first report that low level copy number increases are common in diffuse large B-cell lymphoma and that these changes correlate with MYC mRNA in a statistically significant manner. MYC copy number changes are an additional possible molecular mechanism that may result in increased mRNA and, likely, high proliferation and poor outcome. © F e r r a t a S t o r t i F o u n d a t i o n

The pre-B-cell receptor associated protein VpreB3 is a useful diagnostic marker for identifying c-MYC translocated lymphomas

“…19,20 Second, the association between VpreB3 expression and a subset of DLBCL with c-MYC polysomy raises the possibility that, in a minority of cases, increased c-MYC copy number may partially recapitulate the genetic program of tumors with a c-MYC translocation. 33 Third, our inability to find a direct correlation between VpreB3 and c-Myc transcript abundance in tumors lacking c-MYC genetic abnormalities (Online Supplementary Figure S3) suggests that the expression of VpreB3 may not be directly regulated by the c-Myc protein itself but the result of a broader dysfunctional genetic program in tumors harboring a c-MYC aberration. Further studies are needed to delineate the molecular mechanisms underlying the expression of VpreB3 in these tumors.…”

MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

“…11,19 Furthermore, studies using gene set enrichment analysis showed that high MYC 20,21 Other studies have demonstrated higher levels of MYC mRNA in DLBCL with increased gene copy numbers and correlated these results with an unfavorable prognosis. 22,23 In brief, all these studies indicate the importance of identifying MYC genetic changes in DLBCL. However, most of these studies evaluated only the impact of isolated changes of the MYC gene, were performed in small series of patients, or considered patients treated with CHOP and R-CHOP chemotherapy.…”

“…However, most of these studies evaluated only the impact of isolated changes of the MYC gene, were performed in small series of patients, or considered patients treated with CHOP and R-CHOP chemotherapy. 15,22,23 At the protein level, high expression of MYC detected by immunohistochemistry may be useful to identify cases with MYC translocations. 20,24,25 In this study we investigated the clinical impact of the spectrum of MYC gene alterations and MYC protein expression in DLBCL in comparison to that of other gene alterations.…”

Approach to the diagnosis and treatment of high-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements

“…52,53 However, this has not been consistently shown to be associated with increased MYC protein expression or an inferior clinical outcome. 17,[53][54][55][56][57][58] Other factors can affect MYC levels without directly altering the integrity or location of the MYC locus. Many signaling pathways, including BCR and NF-kB signaling, can lead to increased transcription of MYC through direct and indirect interactions at the MYC promoter as reviewed by Wierstra and Alves.…”