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

Abstract

Background: Translocations 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 methods: Utilizing 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.

Results: Increased 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.

Conclusions: This 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.

Figure 1.

The MYC probe location on chromosome 8q24.

Figure 2

(A) Normal tonsil control with two copies each of MYC (blue) and chromosome 8 centromere (red) per cell (dual color CISH, Nikon Eclipse 80i, x400) Occasional cells have less than two copies due to sectioning of the tissue. (B) Diffuse large B-cell lymphoma with increased MYC gene copy number (blue) relative to chromosome 8 centromere (red) per cell (dual color CISH, Nikon Eclipse 80i, x400). In most cells, clearly separate MYC probes can be discerned.

Figure 3.

Cases were divided into those with increased MYC copy number and not increased MYC copy number by CISH and average MYC mRNA by qNPA was compared between the two groups. The open circle represents the case with a non-IG associated translocation.