Clinical, pathological and genetic features of follicular lymphoma grade 3A: a joint analysis of the German low-grade and high-grade lymphoma study groups GLSG and DSHNHL.
GLA - German Lymphoma Alliance

Abstract (Expand)

BACKGROUND: Histologically, follicular lymphoma (FL) grades 1, 2 and 3A are composed of two distinct cell types, centroblasts and centrocytes. FL grade 3B is composed only of centroblasts and has been … shown to differ in immunophenotype and genetics from FL that contain centrocytes. We aimed to understand the pathogenetic and clinical relation between FL grade 3A to FL grade 1/2 on the one hand and FL grade 3B on the other hand. PATIENTS AND METHODS: Trial patients with long-term follow-up and diagnosis of FL grade 3 were selected and samples underwent a second central pathological review using a multiple-observer approach to assess grading. RESULTS: Interobserver variability for diagnosing FL grade 3 was high. FL grade 3A frequently harbored areas of FL grade 1/2 within the same tissue specimen. FL grade 3B rarely coexisted with grade 1/2 or 3A, suggesting divergent pathogenesis. There was no statistically significant difference in outcome between 47 cases of FL grade 3A and 14 cases of grade 3B. Compared with grade 1/2 FL, both groups showed longer progression-free survival without late events, especially after immunochemotherapy; this outcome difference was retained after adjustment for clinical prognostic factors. The subgroup of FL grade 3A with an additional FL grade 1/2 component or a translocation t(14;18) showed a poorer outcome. In contrast, the FL grade 3A lacking t(14;18) and of localized stage resembled the pediatric type of FL and showed a very good outcome. FL3 with MYC breaks showed a poor outcome. CONCLUSIONS: The results suggest that first-line immunochemotherapy might allow long-lasting remissions in a subgroup of FL grade 3A similar to diffuse large B-cell lymphoma. Within FL3A, prognostic subgroups can be identified by analyzing for coexisting FL1/2 and MYC breaks.

Authors: K. Koch, E. Hoster, M. Ziepert, M. Unterhalt, G. Ott, A. Rosenwald, M. L. Hansmann, W. Bernd, H. Stein, V. Poschel, M. Dreyling, L. Trumper, M. Loffler, N. Schmitz, W. Hiddemann, M. Pfreundschuh, W. Klapper

Date Published: 28th Apr 2016

Publication Type: Not specified

Human Diseases: follicular lymphoma

Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial.
GLA - German Lymphoma Alliance

Abstract (Expand)

Background: There is an on-going debate whether 2- or 3-weekly administration of R-CHOP is the preferred first-line treatment for elderly patients with diffuse large B-cell lymphoma (DLBCL). The UK … NCRI R-CHOP14v21 randomized phase 3 trial did not demonstrate a difference in outcomes between R-CHOP-14 and R-CHOP-21 in newly diagnosed DLBCL patients aged 19-88 years, but data on elderly patients have not been reported in detail so far. Here, we provide a subgroup analysis of patients >/=60 years treated on the R-CHOP14v21 trial with extended follow-up. Patients and methods: Six hundred and four R-CHOP14v21 patients >/=60 years were included in this subgroup analysis, with a median follow-up of 77.7 months. To assess the impact of MYC rearrangements (MYC-R) and double-hit-lymphoma (DHL) on outcome in elderly patients, we performed a joint analysis of cases with available molecular data from the R-CHOP14v21 (N = 217) and RICOVER-60 (N = 204) trials. Results: Elderly DLBCL patients received high dose intensities with median total doses of >/=98% for all agents. Toxicities were similar in both arms with the exception of more grade >/=3 neutropenia (P < 0.0001) and fewer grade >/=3 thrombocytopenia (P = 0.05) in R-CHOP-21 versus R-CHOP-14. The elderly patient population had a favorable 5-year overall survival (OS) of 69% (95% CI: 65-73). We did not identify any subgroup of patients that showed differential response to either regimen. In multivariable analysis including individual factors of the IPI, gender, bulk, B2M and albumin levels, only age and B2M were of independent prognostic significance for OS. Molecular analyses demonstrated a significant impact of MYC-R (HR = 1.96; 95% CI: 1.22-3.16; P = 0.01) and DHL (HR = 2.21; 95% CI: 1.18-4.11; P = 0.01) on OS in the combined trial cohorts, independent of other prognostic factors. Conclusions: Our data support equivalence of both R-CHOP application forms in elderly DLBCL patients. Elderly MYC-R and DHL patients have inferior prognosis and should be considered for alternative treatment approaches. Trial numbers: ISCRTN 16017947 (R-CHOP14v21); NCT00052936 (RICOVER-60).

Authors: A. Kuhnl, D. Cunningham, N. Counsell, E. A. Hawkes, W. Qian, P. Smith, N. Chadwick, A. Lawrie, P. Mouncey, A. Jack, C. Pocock, K. M. Ardeshna, J. Radford, A. McMillan, J. Davies, D. Turner, A. Kruger, P. W. Johnson, J. Gambell, A. Rosenwald, G. Ott, H. Horn, M. Ziepert, M. Pfreundschuh, D. Linch

Date Published: 1st Jul 2017

Publication Type: Not specified

Human Diseases: diffuse large B-cell lymphoma

Dysregulated Signal Propagation in a MYC-associated Boolean Gene Network in B-cell Lymphoma
MMML-MYC-SYS

Abstract (Expand)

By the modern molecular biological approaches that exploit the availability of high quality gene expression data, it is made clear that flexible and robust responses of cellular programs are encoded … in the relations between gene expression values. These relations naturally define a network where they stand for edges between the nodes that stand for the genes. The wiring of these networks often found to be dysregulated in cancer. Different system biological approaches that rely on correlations, differential equations and logical analysis are used to probe these relations in gene expression data especially. In our work we investigated selected biological functions in aggressive germinal center B-cell lymphoma in terms of a logical analysis of gene-regulation in Boolean space and a signal propagation algorithm considering network topology based on gene expression data. We especially aimed at studying the activity of the MYC gene as a key player. It is shown that the functional output of a gene network is affected by the states of the genes and also by the wirings between them. Our results support the key function of MYC in lymphoma biology. In addition, we showed that genes can alter functional output of the network by alternative mechanisms like reducing the variance in propagating signal and locking it to a certain level.

Authors: V. Cakir, H. Loeffler-Wirth, A. Arakelyan, H. Binder

Date Published: 17th May 2017

Publication Type: Not specified

Human Diseases: B-cell lymphoma

Novel IGH and MYC Translocation Partners in Diffuse Large B-Cell Lymphomas.
MMML - Molecular mechanisms in malignant lymphoma

Abstract (Expand)

Chromosomal translocations involving an immunoglobulin (IG) locus and a proto-oncogene play a major role in diffuse large B-cell lymphoma (DLBCL) pathogenesis. Recurrent IG translocation partners in … DLBCL are the BCL6, BCL2, and MYC genes, but other rare translocation partners are also known. We studied 20 DLBCL with fluorescence in situ hybridization-based evidence for IG heavy chain (IGH) locus-associated translocations not involving BCL6, BCL2, MALT1, or MYC by long distance inverse PCR to identify the translocation partners. Moreover, we studied eight DLBCL with MYC translocations not involving IG or known non-IG loci as translocation partner to search for novel MYC translocations. We identified three novel IGH-associated translocations. Chromosomal breakpoints involved the IMMP2L gene in 7q31, the BCAS2 gene in 1p13, and the PVRL2 gene in 19q13. The latter gene, which is recurrently translocated in T-cell lymphomas, is significantly higher expressed in the biopsy with the translocation compared to cases without this genetic aberration, indicating a pathogenetic role of PVRL2 also in DLBCL. In one case with a MYC break we obtained a novel MYC-SOCS1 translocation representing an unusual translocation of a proto-oncogene with a tumor suppressor gene. Indeed, we demonstrate that the oncogene was deregulated and the tumor suppressor gene inactivated. As both genes undergo aberrant somatic hypermutation in the region of the chromosomal breakpoints, this translocation likely happened as a byproduct of the hypermutation process. Overall, our study suggests that chromosomal translocations in DLBCL are more heterogeneous than previously known. (c) 2016 Wiley Periodicals, Inc.

Authors: C. Otto, R. Scholtysik, R. Schmitz, M. Kreuz, C. Becher, M. Hummel, A. Rosenwald, L. Trumper, W. Klapper, R. Siebert, R. Kuppers

Date Published: 30th Jun 2016

Publication Type: Journal article

Human Diseases: diffuse large B-cell lymphoma

Biological characterization of adult MYC-translocation-positive mature B-cell lymphomas other than molecular Burkitt lymphoma.
MMML - Molecular mechanisms in malignant lymphoma

Abstract (Expand)

Chromosomal translocations affecting the MYC oncogene are the biological hallmark of Burkitt lymphomas but also occur in a subset of other mature B-cell lymphomas. If accompanied by a chromosomal break … targeting the BCL2 and/or BCL6 oncogene these MYC translocation-positive (MYC(+)) lymphomas are called double-hit lymphomas, otherwise the term single-hit lymphomas is applied. In order to characterize the biological features of these MYC(+) lymphomas other than Burkitt lymphoma we explored, after exclusion of molecular Burkitt lymphoma as defined by gene expression profiling, the molecular, pathological and clinical aspects of 80 MYC-translocation-positive lymphomas (31 single-hit, 46 double-hit and 3 MYC(+)-lymphomas with unknown BCL6 status). Comparison of single-hit and double-hit lymphomas revealed no difference in MYC partner (IG/non-IG), genomic complexity, MYC expression or gene expression profile. Double-hit lymphomas more frequently showed a germinal center B-cell-like gene expression profile and had higher IGH and MYC mutation frequencies. Gene expression profiling revealed 130 differentially expressed genes between BCL6(+)/MYC(+) and BCL2(+)/MYC(+) double-hit lymphomas. BCL2(+)/MYC(+) double-hit lymphomas more frequently showed a germinal center B-like gene expression profile. Analysis of all lymphomas according to MYC partner (IG/non-IG) revealed no substantial differences. In this series of lymphomas, in which immunochemotherapy was administered in only a minority of cases, single-hit and double-hit lymphomas had a similar poor outcome in contrast to the outcome of molecular Burkitt lymphoma and lymphomas without the MYC break. Our data suggest that, after excluding molecular Burkitt lymphoma and pediatric cases, MYC(+) lymphomas are biologically quite homogeneous with single-hit and double-hit lymphomas as well as IG-MYC and non-IG-MYC(+) lymphomas sharing various molecular characteristics.

Authors: S. M. Aukema, M. Kreuz, C. W. Kohler, M. Rosolowski, D. Hasenclever, M. Hummel, R. Kuppers, D. Lenze, G. Ott, C. Pott, J. Richter, A. Rosenwald, M. Szczepanowski, C. Schwaenen, H. Stein, H. Trautmann, S. Wessendorf, L. Trumper, M. Loeffler, R. Spang, P. M. Kluin, W. Klapper, R. Siebert

Date Published: 2nd Nov 2013

Publication Type: Not specified

Human Diseases: non-Hodgkin lymphoma, diffuse large B-cell lymphoma

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