Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). To identify genes with mutations in B-cell NHL we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase. 11.4% of DLBCL and 13.4% of FL cases had somatic mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis thus suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis.

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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 ...

Segmental copy-number variations (CNVs) in the human genome are associated with developmental disorders and susceptibility to diseases. More importantly, CNVs may represent a major genetic component of our phenotypic diversity. In this study, using a whole-genome array comparative genomic hybridization assay, we identified 3,654 autosomal segmental CNVs, 800 of which appeared at a frequency of at least 3%. Of these frequent CNVs, 77% are novel. In the 95 individuals analyzed, the two most diverse genomes differed by at least 9 Mb in size or varied by at least 266 loci in content. Approximately 68% of the 800 polymorphic regions overlap with genes, which may reflect human diversity in senses (smell, hearing, taste, and sight), rhesus phenotype, metabolism, and disease susceptibility. Intriguingly, 14 polymorphic regions harbor 21 of the known human microRNAs, raising the possibility of the contribution of microRNAs to phenotypic diversity in humans. This in-depth survey of CNVs across the human genome provides a valuable baseline for studies involving human genetics.

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.

The BCL6 transcriptional repressor is required for development of germinal center (GC) B cells and when expressed constitutively causes diffuse large B-cell lymphomas (DLBCLs). We examined genome-wide BCL6 promoter binding in GC B cells versus DLBCLs to better understand its function in these settings.

Mantle cell lymphoma (MCL) is a relatively uncommon yet distinct type of malignant lymphoma whose clinical and pathological characterization has been limited by the small numbers of cases published to date. We studied 80 cases of MCL seen at a single institution over 7 years to determine both clinical and pathological prognostic factors. The patients in this study were predominantly male (70%) and older (mean age, 63 years) and presented with advanced-stage disease (88%). Extranodal involvement was common. Median overall survival (OS) was 43 months. Except for performance status, prognosis was not significantly influenced by clinical prognostic factors. Histologically, MCL architecture was classified as diffuse (78%), nodular (16%), or mantle zone (6%); the OS among these groups was identical. Increased mitotic activity (<20 mitotic figures per 10 high power fields), blastic transformation, and peripheral blood involvement at diagnosis also predicted for a worse outcome, but bone marrow involvement did not. The presence or absence of a translocation t(11; 14) by cytogenetic analysis or a bcl-1 rearrangement by Southern analysis did not significantly predict outcome. In summary, this study of 80 cases of MCL highlights its distinctive clinicopathologic features and shows that increased mitotic activity, blastic morphology, and peripheral blood involvement at diagnosis are prognostically important factors.

Treating all DLBCL as a single entity ignores the mechanistic differences in BCL2 upregulation and obscures the prognostic significance of BCL2 expression. Hence, the significance of BCL2 and other biomarkers should be assessed in the context of DLBCL subgroups in future studies.