Abstract
Diffuse large B-cell lymphoma (DLBCL) is a clinically and genetically heterogeneous disease. Frequent genetic lesions include alterations of BCL2 and BCL6, as well as aberrations of the RB pathway and the p53 pathway resulting in deregulation of cell cycle progression and apoptosis. MYC translocations and amplifications have been detected in a subset of cases. Recently, MYC was shown to control a major regulatory network in B-cells (Nature Genet. 37; 382–90: 2005). We thus hypothesized that DLBCLs with constitutively active MYC are associated with distinctive genetic and clinical features when compared to cases with wild-type MYC. Thirty seven de novo DLBCLs were analyzed using immunohistochemistry for CD10, bcl6, MUM1, and bcl2 expression, as well as fluorescence in situ hybridization for MYC, BCL2, BCL6, IGH, IGK, and IGL breakpoints and amplifications. The lymphomas were previously extensively characterized for aberrations at the genetic, epigenetic, or protein level of components of the RB pathway (pRb, p16, cyclin D3, cdk4) and the p53 pathway (p53, p14ARF, MDM2, E2F1). Five cases (14%) had MYC alterations (4 breakpoints and 1 amplification). Of the MYC+ DLBCL cases, 2 showed GCB immunophenotype and 3 were of non-GCB type. Perturbation of the p53 pathway components p53, p14ARF, MDM2, and E2F1 were identified in 28%, 16%, 53%, and 20% of the MYC− cases, respectively, and 83% had aberrations of 1 or more p53 pathway component. In contrast, only 1 (20%) of the MYC+ cases had a p53 pathway aberration (MDM2 overexpression; p=0.013). Thus, MYC alterations and p53 pathway aberrations were inversely correlated. RB pathway aberrations were equally frequent among MYC+ (40%) and MYC− (43%) DLBCLs. However, the pattern of aberrations was different. Lack of pRb expression was the only alteration of the RB pathway in the MYC+ DLBCLs, whereas 30 of 31 (97%) MYC− lymphomas had normal pRb expression (p=0.045). p16 alterations (point mutation, deletion, hypermethylation, lack of expression) and/or cyclin D3 overexpression were identified in 12 (38%) MYC− cases but in none of the MYC+ cases (p=0.038). MYC status was also related to cytogenetic BCL2 alterations. Four of 5 (80%) MYC+ DLBCLs showed BCL2 breakpoints or amplification in contrast to 4 of 32 (13%) of MYC− DLBCLs (p=0.005). Furthermore, all MYC+ DLBCLs were bcl2 positive (p=0.05) and MUM1 negative (p=0.022), and the proliferation index was lower in the MYC+ DLBCLs (p=0.038). Clinically, MYC+ DLBCL patients were characterized by advanced stage disease (p=0.037) and high tumor burden (p=0.037) but favorable treatment response (p=0.05). Taken together, our data indicate that DLBCL with MYC alterations constitute a subgroup of DLBCL with distinct clinical and molecular features. The patterns of aberrations of the p53 pathway, the RB pathway, and BCL2 indicate profound differences in the molecular pathogenesis between MYC+ and MYC− DLBCL.
Clinical features, tumor biology, and prognosis associated with MYC rearrangement and Myc overexpression in diffuse large B-cell lymphoma patients treated with rituximab-CHOP