Diffuse large B-cell lymphoma (DLBCL) can be divided into prognostically important subgroups with germinal center Bcell-like (GCB), activated B-cell-like (ABC), and type 3 gene expression profiles using a cDNA microarray. Tissue microarray (TMA) blocks were created from 152 cases of DLBCL, 142 of which had been successfully evaluated by cDNA microarray (75 GCB, 41 ABC, and 26 type 3). Sections were stained with antibodies to CD10, bcl-6, MUM1, FOXP1, cyclin D2, and bcl-2. Expression of bcl-6 (P < .001) or CD10 (P ‫؍‬ .019) was associated with better overall survival (OS), whereas expression of MUM1 (P ‫؍‬ .009) or cyclin D2 (P < .001) was associated with worse OS. Cases were subclassified using CD10, bcl-6, and MUM1 expression, and 64 cases (42%) were considered GCB and 88 cases (58%) non-GCB. The 5-year OS for the GCB group was 76% compared with only 34% for the non-GCB group (P < .001), which is similar to that reported using the cDNA microarray. Bcl-2 and cyclin D2 were adverse predictors in the non-GCB group. In multivariate analysis, a high International Prognostic Index score (3-5) and the non-GCB phenotype were independent adverse predictors (P < .0001). In summary, immunostains can be used to determine the GCB and non-GCB subtypes of DLBCL and predict survival similar to the cDNA microarray. IntroductionDiffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and accounts for 30% to 40% of new diagnoses. 1,2 However, DLBCL is heterogeneous both clinically and morphologically. Despite the use of anthracycline-based chemotherapy, durable remissions are achieved in only 40% to 50% of patients. 2 Therefore, it is important to identify at diagnosis those patients who may benefit from more aggressive or experimental therapies.Currently, the prognosis of patients with DLBCL is estimated using the clinical parameters of the International Prognostic Index (IPI). 3 However, these clinical parameters reflect a mixture of underlying biologic or genetic differences. In an attempt to elucidate these underlying factors, the prognostic value of numerous individual proteins has been studied by immunoperoxidase and molecular techniques. However, these studies have yielded conflicting results, and none have been validated in a large prospective trial. Therefore, in contrast to the IPI, these individual markers are generally not used in clinical practice for selecting therapy or predicting prognosis.Using a cDNA microarray, DLBCL can be divided into prognostically significant subgroups with germinal center B-celllike (GCB), activated B-cell-like (ABC), or type 3 gene expression profiles. 35,36 The GCB group has a significantly better survival than the ABC group. The type 3 group is heterogeneous and not well defined, but has a poor outcome similar to the ABC group. Another study using an oligonucleotide array has demonstrated that DLBCL can be divided into 2 molecularly distinct populations (cured and fatal/refractory). 37 Because this technology is expensive and not generally available, a sim...

Background-Despite advances in treatments for Hodgkin's lymphoma, about 20% of patients still die from progressive disease. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on the International Prognostic Score.

Approximately 5% to 10% of diffuse large B-cell lymphomas (DLBCLs) harbor an MYC oncogene rearrangement (MYC ؉ ). The prognostic significance of MYC ؉ DLBCL was determined in an unselected population of patients with newly diagnosed DLBCL treated with rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy (R-CHOP). Using a Vysis break-apart fluorescence in situ hybridization probe, 12 of 135 (8.8%) cases of MYC ؉ DLBCL were identified that had no defining high-risk features. MYC ؉ DLBCL was associated with an inferior 5-year progression-free survival (66% vs 31%, P ‫؍‬ .006) and overall survival (72% vs 33%, P ‫؍‬ .016). Multivariate analysis confirmed the prognostic importance of MYC for both progression-free survival (hazard ratio ‫؍‬ 3.28; 95% confidence interval, 1.49-7.21, P ‫؍‬ .003) and overall survival (hazard ratio ‫؍‬ 2.98; 95% confidence interval, 1.28-6.95, P ‫؍‬ .011). Cases of MYC ؉ DLBCL also had a higher risk of central nervous system relapse (P ‫؍‬ . IntroductionDiffuse large B-cell lymphomas (DLBCLs) are recognized to be a heterogeneous group of diseases with clinical, morphologic, immunohistochemical, and molecular subtypes defined in the updated World Health Organization (WHO) classification. 1 Further, a new category has been created defined as "borderline cases," which are considered B-cell lymphomas, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma. 2 Morphologically, these tumors typically have a mixture of medium-to large-sized cells, a high proliferation rate, and 35% to 50% of cases have an 8q24/MYC translocation. 2 However, approximately 5% to 10% of DLBCLs with typical morphology also harbor an MYC rearrangement (herein after referred to as MYC ϩ ), and these cases are considered in the category of DLBCL, not otherwise specified, in the updated WHO classification. 3 There is very little information regarding the prognostic importance of an isolated MYC rearrangement in DLBCL using modern diagnostic criteria. A recent study suggested that MYC gene rearrangements identified by fluorescence in situ hybridization (FISH) in pathologically defined DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP)-like chemotherapy are associated with an inferior prognosis. 4 However, it is unclear whether there are identifiable clinical or pathologic characteristics that suggest that a case may harbor an MYC rearrangement to prompt evaluation. Further, prior studies evaluating the prognostic implications of MYC in DLBCL have been performed before the use of rituximab. With studies showing improved outcome using rituximab in combination with CHOP (R-CHOP) or CHOP-like therapies in the treatment of DLBCL, 5-8 the importance of MYC rearrangement status in this population must be reestablished.The purpose of this study was 2-fold: (1) to screen an unselected series of patients with DLBCL for MYC rearrangements to determine the frequency of this occurrence and whether there were any pathologic or ...

Chromosomal translocations are critically involved in the molecular pathogenesis of B-cell lymphomas, and highly recurrent and specific rearrangements have defined distinct molecular subtypes linked to unique clinicopathological features1,2. In contrast, several well-characterized lymphoma entities still lack disease-defining translocation events. To identify novel fusion transcripts resulting from translocations, we investigated two Hodgkin lymphoma cell lines by whole-transcriptome paired-end sequencing (RNA-seq). Here we show a highly expressed gene fusion involving the major histocompatibility complex (MHC) class II transactivator CIITA (MHC2TA) in KM-H2 cells. In a subsequent evaluation of 263 B-cell lymphomas, we also demonstrate that genomic CIITA breaks are highly recurrent in primary mediastinal B-cell lymphoma (38%) and classical Hodgkin lymphoma (cHL) (15%). Furthermore, we find that CIITA is a promiscuous partner of various in-frame gene fusions, and we report that CIITA gene alterations impact survival in primary mediastinal B-cell lymphoma (PMBCL). As functional consequences of CIITA gene fusions, we identify downregulation of surface HLA class II expression and overexpression of ligands of the receptor molecule programmed cell death 1 (CD274/PDL1 and CD273/PDL2). These receptor–ligand interactions have been shown to impact anti-tumour immune responses in several cancers3, whereas decreased MHC class II expression has been linked to reduced tumour cell immunogenicity4. Thus, our findings suggest that recurrent rearrangements of CIITA may represent a novel genetic mechanism underlying tumour–microenvironment interactions across a spectrum of lymphoid cancers.

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