Focused Gene Expression Profiling of Diffuse Large B-Cell Lymphoma with MYC Rearrangement
Tina M Green, Karin de Stricker, Ken H Young, Michael B Moeller. Odense University Hospital, Odense, Denmark; University of Southern Denmark, Odense, Denmark; The University of Texas MD Anderson Cancer Center, Houston, TX
Background: MYC translocation is a putative marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). The gene expression patterns accompanying MYC translocations in DLBCL have not been fully elucidated. Here we used quantitative real-time PCR (QRT-PCR) to investigate differential gene expression patterns in DLBCL with (MYC+) and without (MYC-) cytogenetic MYC rearrangement.
Design: 194 primary DLBCLs patients with app. 5 years of follow up were included. All patients had received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (R-CHOP). All tumors were analyzed for presence of MYC rearrangement using FISH. Cell-of-origin subtype was determined by immunohistochemistry (Hans algorithm). Clinical characteristics were compared between MYC+ and MYC- groups (Fischer's exact test). All tumors were investigated by QRT-PCR, measuring transcript levels of 28 potentially prognostic genes. Differential gene expression between MYC+ and MYC- tumors was calculated using the delta-deltaCt method. Univariate survival analysis was done using the Kaplan-Meier method. The level of significance was set to 0.05.
Results: Rearrangement of MYC was found in 12% of the tumors. MYC+ patients were characterized by an aggressive clinical phenotype with higher LDH (P= 0.022), stage (P=0.021) and IPI (P=0.006), and associated with an inferior 5-year overall survival (50.6% vs 67.5%, P=0.034). 82 % of MYC+ tumors were germinal B-cell (GCB) type (P= 0.012). MYC+ tumors showed significant overexpression of CD10 (4.6 fold), BCL2 (1.8 fold), and NPM3 (1.7 fold). Three putative good-prognosis genes, LMO2, HLA-DQA1, and ACTN1 were significantly underexpressed (3.3 fold, 2.6 fold, and 1.9 fold) in the MYC+ group. Also, the non-GCB markers SPIB and CCND2 were significantly underexpressed (1.8 and 2.6 fold).
Conclusions: The clinical characteristics of MYC+ cases are in accordance with previous studies. The relative underexpression of LMO2 and HLA-DQA1 in cases with MYC rearrangement is surprising because these are considered to be GCB markers. Recent studies have found LMO2 to be a strong predictor of good prognosis and low expression may be related to the poor prognosis in MYC+ cases although no direct link between MYC and LMO2 has been described. HLA-DQA1 is involved in immune surveillance. Low levels of HLA-genes are a prominent feature of DLBCLs with an aggressive clinical course, such as CNS and testicular lymphomas.
Monday, March 19, 2012 8:30 AM
Platform Session: Section C, Monday Morning