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MYCdysregulation, including MYCgene rearrangement and Myc protein overexpression, is of increasing clinical importance in diffuse large B-cell lymphoma (DLBCL). However, the roles of MYC and the relative importance of rearrangement vsoverexpression remain to be refined. Gaining knowledge about the tumor biology associated with MYCdysregulation is important to understand the roles of MYC and MYC-associated biology in lymphomagenesis. In this study, we determined MYCrearrangement status (n=344) and Myc expression (n=535) in a well-characterized DLBCL cohort, individually assessed the clinical and pathobiological features of patients with MYCrearrangement and Myc protein overexpression, and analyzed the prognosis and gene expression profiling signatures associated with these MYC abnormalities in germinal center B-cell-like and activated B-cell-like DLBCL. Our results showed that the prognostic importance of MYCrearrangement vsMyc overexpression is significantly different in germinal center B-cell-like vsactivated B-cell-like DLBCL. In germinal center B-cell-like DLBCL, MYC-rearranged germinal center B-cell-like DLBCL patients with Myc overexpression significantly contributed to the clinical, biological, and prognostic characteristics of the overall Myc-overexpressing germinal center B-cell-like DLBCL group. In contrast, in activated B-cell-like DLBCL, the occurrence, clinical and biological features, and prognosis of Myc overexpression were independent of MYCrearrangement. High Myc levels and Myc-independent mechanisms, either tumor cell intrinsic or related to tumor microenvironment, conferred significantly worse survival to MYC-rearranged germinal center B-cell-like DLBCL patients, even among MychighBcl-2highDLBCL patients. This study provides new insight into the tumor biology and prognostic effects associated with MYC dysregulation and suggest that detection of both MYCtranslocations and evaluation of Myc and Bcl-2 expression is necessary to predict the prognosis of DLBCL patients.

In order to address the debatable prognostic role of MYCrearrangements in diffuse large B-cell lymphoma patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone, we evaluated MYCrearrangements by fluorescence in situhybridization in 563 cases using break-apart probes and IGH/MYCdual-fusion probes. Concurrent BCL2and BCL6aberrations were also assessed. Data were correlated with clinicopathological variables and prognostic parameters. MYCrearrangements were observed in 39/432 evaluable cases (9%), including 4 rearrangements detectable only with the dual-fusion probes, 15 detectable only with the break-apart probes and 20 detectable with both dual-fusion probes and break-apart probes. MYCrearrangements correlated with germinal center B-cell origin (P=0.02), MYC protein expression (P=0.032), and larger tumor mass size (P=0.0003). Patients with MYCrearrangements were more likely to be treatment resistant (P<0.0001). All types of MYCrearrangements were associated with poorer disease-specific survival, that is, 20/39 dead, median disease-specific survival 42 months, compared with 98/393 dead among the non-rearranged cases, median disease-specific survival not reached (P=0.0002). Cases with MYCrearrangements that overexpressed MYC protein were at risk with respect to disease-specific survival independent of the International Prognostic Index (P=0.046 and P<0.001, respectively). Presence of concurrent BCL2aberrations but not of BCL6aberrations was prognostically additive. Radiotherapy seemed to diminish the prognostic effects of MYCrearrangements in diffuse large B-cell lymphoma patients since only 2/10 irradiated patients with MYCrearrangements died of/with disease, compared with 16/28 non-irradiated patients with MYCrearrangements. We conclude that MYCrearrangements add prognostic information for individual risk estimation and such cases might represent a distinct, biologically determined disease subgroup.

Primary B-cell lymphoma of the testis, breast and thyroid are rare and data concerning cytogenetic aberrations at these extranodal sites are scarce. We examined the presence of extranodal marginal zone lymphoma-associated translocations, t(11;18)(q21;q21), t(1;14)(p22;q32), t(14;18)(q32;q21), t(3;14)(p14.1;q32) and numerical aberrations of chromosomes 1, 3, 12 and 18 by fluorescence in situhybridization in 6 extranodal marginal zone lymphomas and 24 diffuse large B-cell lymphomas with (n=9) or without (n=15) marginal zone lymphoma components, with primary localizations in the breast (n=15), testis (n=9) and thyroid (n=6). We found t(14;18)(q32;q21), with breakpoints in IGHand MALT1, in one testicular diffuse large B-cell lymphoma and in two diffuse large B-cell lymphomas of the breast. No other translocations, amplifications or deletions involving IGH, BCL-10, BCL-2, MALT1and IAP2were detected. Numerical aberrations occurred in 67% of the lymphomas, 67% of extranodal marginal zone lymphomas, 56% of diffuse large B-cell lymphomas with marginal zone lymphoma components and in 73% of ‘de novo' diffuse large B-cell lymphomas. These included 78% of testis, 67% of thyroid and 60% of breast lymphomas, and included mainly trisomy 18 (n=16), trisomy 3 (n=8) and trisomy 1 (n=3). One testicular diffuse large B-cell lymphoma harbored both t(14;18)(q32;q21) and trisomy 3. Our results indicate that at least a few cases of diffuse large B-cell lymphoma of the testis and the breast belong to the spectrum of extranodal marginal zone lymphoma.