Diffuse large B-cell lymphomas with CDKN2A deletion have a distinct gene expression signature and a poor prognosis under R-CHOP treatment: a GELA study

Blood ◽  
2010 ◽  
Vol 116 (7) ◽  
pp. 1092-1104 ◽  
Author(s):  
Fabrice Jardin ◽  
Jean-Philippe Jais ◽  
Thierry-Jo Molina ◽  
Françoise Parmentier ◽  
Jean-Michel Picquenot ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Signature ◽  
Gene Copy ◽  
Specific Gene ◽  
B Cell Lymphomas ◽  
Single Polymerase Chain Reaction ◽  
Expression Signature ◽  
Cdkn2a Deletion ◽  
Large B Cell

Abstract Genomic alterations play a crucial role in the development and progression of diffuse large B-cell lymphomas (DLBCLs). We determined gene copy number alterations (GCNAs) of TP53, CDKN2A, CDKN1B, BCL2, MYC, REL, and RB1 with a single polymerase chain reaction (PCR) assay (quantitative multiplex PCR of short fragments [QMPSF]) in a cohort of 114 patients with DLBCL to assess their prognostic value and relationship with the gene expression profile. Losses of TP53 and CDKN2A, observed in 8% and 35% of patients, respectively, were significantly associated with a shorter survival after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) treatment, independently of the International Prognostic Index and of the cell of origin. Analysis of the 9p21 genomic region indicated that transcripts encoding p14ARF and p16INK4A were both disrupted in most patients with CDKN2A deletion. These patients predominantly had an activated B-cell profile and showed a specific gene expression signature, characterized by dysregulation of the RB/E2F pathway, activation of cellular metabolism, and decreased immune and inflammatory responses. These features may constitute the molecular basis sustaining the unfavorable outcome and chemoresistance of this DLBCL subgroup. Detection of TP53 and CDKN2A loss by QMPSF is a powerful tool that could be used for patient stratification in future clinical trials.

Gene Expression Signature of B-Cell Chronic Lymphocytic Leukemia with Trisomy 12.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2079-2079
Author(s):  
Edit Porpaczy ◽  
Martin Bilban ◽  
Elisabeth Kroemer ◽  
Georg Heinze ◽  
Michaela Gruber ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cells ◽  
B Cell ◽  
Gene Expression Signature ◽  
Fold Change ◽  
Diagnostic Tools ◽  
Marker Genes ◽  
Specific Gene ◽  
Expression Signature ◽  
Trisomy 12

Abstract The prognosis of patients with B-CLL is largely determined by the karyotype of the malignant clone. Microarray technology has facilitated linkage between chromosomal aberrations and gene expression signatures. We have investigated the gene expression profile associated with trisomy 12 (+12). Expression data were obtained by microarray analysis of mRNA from unselected PBMNC of 4 patients with +12 and compared with 16 B-CLL controls. 146 genes were at least 2-fold over- or underexpressed in samples with +12. Five of the 16 genes showing the strongest correlation with +12 were selected for further analysis (HIP1R FC=3,43; MYF6 FC=3,92; P2RY14 FC=−9,59; RASGRP3 FC=−3,85; SLC2A6 FC=2,13) and validation by real time PCR: HIP1R located on chromosome 12q24, with a fold change (FC) of 3,43, MYF6 (chromosome 12q21, FC=3,92), P2RY14 (chromosome 3q21–q25, FC-9,59) RASGRP3 (chromosome 2p25.1–p24.1, FC=−3,85). SLC2A6 (chromosome 9q34, FC=2,13). Quantitative PCR was performed with mRNA from 61 patients (29 with +12, 32 B-CLL controls) and 2 healthy donors. Only 3 genes were significantly associated with +12 compared to the B-CLL-controls in this evaluation: HIP1R (3,486; p<0,0001), MYF6 (1,498; p=0,005), P2RY14 (1,216; p=0,013). (Table1). Two of these genes (HIP1R, MYF6) are located on chromosome 12 indicating a “gene dosage effect”, while P2RY14 is localized on a different chromosome suggesting trans-acting processes. We have used expression of HIP1R as a surrogate marker for trisomy 12. The predicted sensitivity was 79,3% and the predicted specifity was 90,6. Analysis of CD19+ selected B-CLL and normal B-cells revealed that MYF6 is exclusively expressed in normal or malignant B-cells in peripheral blood. We confirmed that MYF6 is highly specific for skeletal muscle, however strong expression was found in normal tonsils, DLBCL, and other B-cell malignancies. Our data link a specific gene expression signature with trisomy 12. 3 novel marker genes were identified, which could be used as diagnostic tools. The linkage with P2RY14 suggests that +12 influences the expression of genes from other chromosomes. Table 1 Mean + 12, N=29 Mean B-CLL controls, N=32 p-value Locus Fold change microarray HIP1R 0,7819 0,2243 0,000 12q24 3,43 MYF6 37,55 25,06 0,005 12q21 3,92 P2RY14 −0,2873 0,3494 0,013 3q21–q25 −9,59 RASGRP3 0,8404 1,0774 0,055 2p25.1–p24.1 −3,85 SLC2A6 29,78 22,37 0,080 9q34 2,13

scholarly journals The double-hit signature identifies double-hit diffuse large B-cell lymphoma with genetic events cryptic to FISH

Blood ◽  
2019 ◽  
Vol 134 (18) ◽  
pp. 1528-1532 ◽  
Author(s):  
Laura K. Hilton ◽  
Jeffrey Tang ◽  
Susana Ben-Neriah ◽  
Miguel Alcaide ◽  
Aixiang Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Signature ◽  
B Cell Lymphoma ◽  
B Cell Lymphomas ◽  
Germinal Center B Cell ◽  
Genetic Mechanisms ◽  
Double Hit ◽  
Poor Outcomes ◽  
Large B Cell

Abstract High-grade B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements (HGBL-DH/THs) include a group of diffuse large B-cell lymphomas (DLBCLs) with inferior outcomes after standard chemoimmunotherapy. We recently described a gene expression signature that identifies 27% of germinal center B-cell DLBCLs (GCB-DLBCLs) as having a double-hit–like expression pattern (DHITsig) and inferior outcomes; however, only half of these cases have both MYC and BCL2 translocations identifiable using standard breakapart fluorescence in situ hybridization (FISH). Here, 20 DHITsig+ GCB-DLBCLs apparently lacking MYC and/or BCL2 rearrangements underwent whole-genome sequencing. This revealed 6 tumors with MYC or BCL2 rearrangements that were cryptic to breakapart FISH. Copy-number analysis identified 3 tumors with MYC and 6 tumors with MIR17HG gains or amplifications, both of which may contribute to dysregulation of MYC and its downstream pathways. Focal deletions of the PVT1 promoter were observed exclusively among DHITsig+ tumors lacking MYC translocations; this may also contribute to MYC overexpression. These results highlight that FISH fails to identify all HGBL-DH/THs, while revealing a range of other genetic mechanisms potentially underlying MYC dysregulation in DHITsig+ DLBCL, suggesting that gene expression profiling is more sensitive for identifying the biology underlying poor outcomes in GCB-DLBCL.

Gene expression profiling of diffuse large B-Cell lymphomas supervised by CD5 expression

2015 ◽  
Vol 102 (2) ◽  
pp. 188-194 ◽  
Author(s):  
Kana Miyazaki ◽  
Motoko Yamaguchi ◽  
Hiroshi Imai ◽  
Kyoko Kobayashi ◽  
Satoshi Tamaru ◽  
...  
Keyword(s):  
Gene Expression ◽  
B Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
B Cell Lymphomas ◽  
Large B Cell

scholarly journals High BAALC expression associates with other molecular prognostic markers, poor outcome, and a distinct gene-expression signature in cytogenetically normal patients younger than 60 years with acute myeloid leukemia: a Cancer and Leukemia Group B (CALGB) study

Blood ◽  
2008 ◽  
Vol 111 (11) ◽  
pp. 5371-5379 ◽  
Author(s):  
Christian Langer ◽  
Michael D. Radmacher ◽  
Amy S. Ruppert ◽  
Susan P. Whitman ◽  
Peter Paschka ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Gene Expression Signature ◽  
Specific Gene ◽  
Stem Cell Markers ◽  
Inverse Association ◽  
Expression Signature ◽  
Acute Myeloid

AbstractBAALC expression is considered an independent prognostic factor in cytogenetically normal acute myeloid leukemia (CN-AML), but has yet to be investigated together with multiple other established prognostic molecular markers in CN-AML. We analyzed BAALC expression in 172 primary CN-AML patients younger than 60 years of age, treated similarly on CALGB protocols. High BAALC expression was associated with FLT3-ITD (P = .04), wild-type NPM1 (P < .001), mutated CEBPA (P = .003), MLL-PTD (P = .009), absent FLT3-TKD (P = .005), and high ERG expression (P = .05). In multivariable analysis, high BAALC expression independently predicted lower complete remission rates (P = .04) when adjusting for ERG expression and age, and shorter survival (P = .04) when adjusting for FLT3-ITD, NPM1, CEBPA, and white blood cell count. A gene-expression signature of 312 probe sets differentiating high from low BAALC expressers was identified. High BAALC expression was associated with overexpression of genes involved in drug resistance (MDR1) and stem cell markers (CD133, CD34, KIT). Global microRNA-expression analysis did not reveal significant differences between BAALC expression groups. However, an analysis of microRNAs that putatively target BAALC revealed a potentially interesting inverse association between expression of miR-148a and BAALC. We conclude that high BAALC expression is an independent adverse prognostic factor and is associated with a specific gene-expression profile.

scholarly journals M17, a gene specific for germinal center (GC) B cells and a prognostic marker for GC B-cell lymphomas, is dispensable for the GC reaction in mice

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4849-4856 ◽  
Author(s):  
Dominik Schenten ◽  
Angela Egert ◽  
Manolis Pasparakis ◽  
Klaus Rajewsky
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Gene Expression Signature ◽  
Antibody Responses ◽  
B Cell Lymphomas ◽  
Clinical Prognosis ◽  
V Region

AbstractIn T-cell–dependent antibody responses, antigen-specific B cells undergo a phase of secondary antibody diversification in germinal centers (GCs). Somatic hypermutation (SHM) introduces mutations into the rearranged immunoglobulin (Ig) variable (V) region genes, and class-switch recombination (CSR) alters the Ig heavy (H) chain constant region. Aberrant SHM or CSR is thought to contribute to the development of GC-derived B-cell malignancies. Diffuse large B-cell lymphomas (DLBCLs) are a heterogeneous group of such GC-derived tumors. Based on their gene expression profile, DLBCLs can be divided into activated B-cell–like and GC-like subgroups. The human gene HGAL is predominantly expressed in GCs. It is also part of the gene expression signature of GC-like DLBCL, and its high expression in DLBCL has been associated with a better clinical prognosis. We have generated mice deficient of the HGAL homologue M17 in order to investigate its functional significance. The mutant animals form normal GCs, undergo efficient CSR and SHM, and mount T-cell–dependent antibody responses similar to wild-type controls. Thus, M17 is dispensable for the GC reaction, and its potential function in the pathogenesis of DLBCL remains elusive.

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