MYC Gene Copy Increase Is Common in Diffuse Large B-Cell Lymphoma
CJ Stasik, H Nitta, JR Cook, RR Tubbs, TM Grogan, LM Rimsza. University of Arizona, Tucson, AZ; Ventana Medical Systems, Inc., Tucson, AZ; Cleveland Clinic, Cleveland, OH
Background: Recently, mRNA expression levels of candidate genes identified in the literature as having prognostic significance in diffuse large B cell lymphoma (DLBCL) were evaluated. HLADRB and MYC emerged as independent indicators of survival and formed a strong 2-gene model of outcome prediction (Rimsza et al, Blood 2008). Possible mechanisms of MYC over-expression in DLBCL include t(8;14)IGH/MYC, increased MYC copy number and chromosome 8 hyperploidy. In this study, cases with known MYC expression levels were evaluated in order to evaluate the underlying mechanisms.
Design: Thirteen DLBCL cases (labeled A through M) were identified with known MYC gene expression status and separated into high (7) and normal (6) MYC groups. Mechanisms for MYC over-expression were evaluated using fluorescence in-situ hybridization (FISH) for chromosome 8 ploidy, MYC gene alterations using a breakapart MYC probe, or the presence of t(8;14) IGH/MYC using fusion probes. Silver in-situ hybridization (SISH, Ventana Medical Systems, Tucson, AZ) for MYC was used to evaluate the original 13 cases as well as 40 additional DLBCL cases (tissue microarray) for increased MYC copy number.
Results: FISH screening utilizing a break-apart probe demonstrated one case (H) with a MYC translocation not involving the 14q32.3 IGH locus. Fusion probes were used to evaluate MYC copy number and chromosome 8 (CEP8) and the MYC/CEP8 ratio was calculated. Two cases (H and I) had increased MYC and CEP8 signals with a MYC/CEP8 ratio near 1. Further FISH analysis revealed 3/13 cases with trisomy 8 (F, H, I), two cases with an extra MYC signal and normal chromosome 8 number (F, H) and one case with a borderline number of nuclei demonstrating tetrasomy 8 (I). SISH found 2/13 cases with increased MYC copy number (H, I). No cases with normal MYC levels had increased MYC copy number or chromosome 8 hyperploidy. Analysis of additional cases by SISH found increased MYC gene copy number in 20/40 cases.
Conclusions: Trisomy 8 or increased MYC copy number was shown in 43% of cases with increased MYC expression and 50% of cases with unknown expression. The remaining cases with increased MYC levels did not show MYC or chromosome 8 alterations implying MYC upregulation may occur by alternate mechanisms. Chromosome 8 hyperploidy and/or increased MYC gene copy number likely represent common mechanisms of MYC gene over-expression in DLBCL.
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 171, Wednesday Morning