Prognostic significance of biomarkers of diffuse large B-cell lymphomas

2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 9639-9639
Author(s):  
S. Kim ◽  
S.-E. Park ◽  
J. S. Kim ◽  
S. K. Kwak ◽  
H. J. Yun ◽  
...  
2007 ◽  
Vol 2 ◽  
pp. 117727190700200 ◽  
Author(s):  
Alexandar Tzankov ◽  
Philip Went ◽  
Stephan Dirnhofer

Diffuse large B-cell lymphomas (DLBCL) are the most common lymphoid malignancies, and encompass all malignant lymphomas characterized by large neoplastic cells and B-cell derivation. In the last decade, DLBCL has been subjected to intense clinical, phenotypic and molecular studies, and were found to represent a heterogeneous group of tumors. These studies suggested new disease subtypes and variants with distinct clinical characteristics, morphologies, immunophenotypes, genotypes or gene expression profiles, associated with distinct prognoses or unique sensitivities to particular therapy regimens. Unfortunately, the reliability and reproducibility of the molecular results remains unclear due to contradictory reports in the literature resulting from small sample sizes, referral and selection biases, and variable methodologies and cut-off levels used to determine positivity. Here, we review phenotypic studies on the prognostic significance of protein expression profiles in DLBCL and reconsider our own retrospective data on 301 primary DLBCL cases obtained on a previously validated tissue microarray in light of powerful statistical methods of determining optimal cut-off values of phenotypic factors for prediction of outcome.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3007-3007
Author(s):  
Aine McCarthy ◽  
Andrew James Clear ◽  
Jacek Marzec ◽  
Rita Coutinho ◽  
Robert D. Petty ◽  
...  

Abstract Background: Human follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the most common forms of indolent and aggressive NHL, respectively. The t(14;18) translocation characterizes approximately 85% of FL and 20% of DLBCL and results in constitutive overexpression of the anti-apoptotic protein BCL-2. It was previously reported that BCL-2 plays dual roles in preventing apoptosis and autophagy. Autophagy is a physical and pathological process whereby cells sequester portions of cytoplasm including organelles to form autophagosomes where they are degraded and recycled. Growing evidence demonstrates that autophagy plays important roles in tumorigenesis, tumor progression, and resistance to chemotherapy. Aims: The autophagy status in human B-cell lymphomas is unknown. We hypothesized that overexpression of BCL-2 could change autophagy status and aimed to determined expression of autophagy-related genes and proteins in FL and DLBCL primary samples by PCR array and tissue microarray. We aimed to evaluate whether expression of the autophagy-related proteins p62, Beclin-1 and LC3 individually and in combination with BCL-2 protein expression could risk-stratify FL and DLBCL patients at diagnosis. Patients and methods: Using PCR array, the autophagy-related gene expression profiles were determined in purified and unpurified reactive and malignant human lymph node tissue biopsies. Diagnostic tissues from FL (n=117) and DLBCL (n=109) patients were microarrayed and autophagy protein expression was evaluated using immunohistochemistry. Univariate and multivariate analyses on both continuous and categorical variables were conducted to measure overall survival (OS), disease specific survival (DSS), and progression-free survival (PFS). Results: Seven autophagy machinery genes were up-regulated in purified FL B-cells, namely ATG9A, ATG16L1, MAP1LC3A, GABARAPL1, ULK1, LAMP1 and HDAC6 compared with reactive B-cells. Two autophagy machinery genes, MAP1LC3A and DRAM1, were up-regulated in DLBCL B-cells. In unpurified tissue biopsies, 20 of 46 genes in FL and 2 of 5 genes in DLBCL with increased expression were autophagy machinery genes. CTSD (cathepsin D) and TGM2 (transglutaminase 2) genes and proteins were mainly up-regulated in DLBCL tumor-infiltrating macrophages. These results demonstrate that FL and DLBCL showed increased expression of autophagy-related genes, regardless of the heterogeneity of these diseases. p62, a selective autophagy substrate; LC3, an autophagosome membrane protein; and Beclin-1, an essential autophagy effector, are often used to evaluate autophagy activity in the cell. 91% FL samples were BCL-2 positive but significantly decreased expression of p62, LC3 and Beclin-1 in FL samples was observed in both intra-follicular and non-malignant inter-follicular areas. This suggests that increased basal autophagy activity in both malignant FL cells and surrounding tumor infiltrating cells, indicating that BCL-2 does not inhibit basal autophagy activity. DLBCL samples displayed heterogeneous expression patterns of BCL-2, p62, LC3 and Beclin-1. We found that decreased p62 expression confers worse OS (continuous P=0.015; and categorical P=0.003), DSS (continuous P=0.037; categorical P=0.014) and PFS (categorical P=0.002) in DLBCL patients. Decreased expression of Beclin-1 was also confers poor prognosis in both FL and DLBCL as conducted by categorical analysis, OS (DLBCL, P=0.015; FL, P=0.004), DSS (FL, P=0.006), and PFS (DLBCL, P=0.029). p62 retains prognostic significance after adjustment for the International Prognostic Index (IPI) score and levels of BCL-2, Beclin-1 and LC3 in multivariate analysis. Beclin-1 retains its prognostic significance in FL after adjusting for FLIPI scores. Low p62 plus high BCL-2 expression in DLBCL confers the worst OS (P<0.0001) and DSS (P=0.001) compared with other combinations. Conclusions: These results demonstrate that FL has increased basal autophagy activity, while it varies in DLBCL. p62 is a novel, independent prognostic biomarker for DLBCL but not for FL. Combining p62 with BCL-2 provides a more robust and reliable method to risk-stratify DLBCL patients at diagnosis. Importantly, we report for the first time that overexpression of BCL-2 in human NHL does not inhibit basal autophagy activity. We propose that increased autophagy activity could be a therapeutic target for treatment of NHL. Disclosures Gribben: Celgene: Research Funding; Pharmacyclics: Honoraria; Roche: Honoraria.


2004 ◽  
Vol 22 (14_suppl) ◽  
pp. 9639-9639
Author(s):  
S. Kim ◽  
S.-E. Park ◽  
J. S. Kim ◽  
S. K. Kwak ◽  
H. J. Yun ◽  
...  

2008 ◽  
Vol 19 (10) ◽  
pp. 1774-1786 ◽  
Author(s):  
K. Amara ◽  
M. Trimeche ◽  
S. Ziadi ◽  
A. Laatiri ◽  
M. Hachana ◽  
...  

2022 ◽  
Author(s):  
Anne M. R. Schrader ◽  
Ruben A. L. de Groen ◽  
Rein Willemze ◽  
Patty M. Jansen ◽  
Koen D. Quint ◽  
...  

Abstract Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) and primary cutaneous follicle center lymphoma with a diffuse population of large cells (PCFCL-LC) are both primary cutaneous B-cell lymphomas with large-cell morphology (CLBCL) but with different clinical characteristics and behavior. In systemic diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS), gene-expression profiling (GEP) revealed two molecular subgroups based on their cell-of-origin (COO) with prognostic significance: the germinal center B-cell-like (GCB) subtype and the activated B-cell-like (ABC) subtype. This study investigated whether COO classification is a useful tool for classification of CLBCL. For this retrospective study, 51 patients with PCDLBCL-LT and 15 patients with PCFCL-LC were analyzed for their COO according to the immunohistochemistry-based Hans algorithm and the NanoString GEP-based Lymph2Cx algorithm. In PCFCL-LC, all cases (100%) classified as GCB by both Hans and Lymph2Cx. In contrast, COO classification in PCDLBCL-LT was heterogeneous. Using Hans, 75% of the PCDLBCL-LT patients classified as non-GCB and 25% as GCB, while Lymph2Cx classified only 18% as ABC, 43% as unclassified/intermediate, and 39% as GCB. These COO subgroups did not differ in the expression of BCL2 and IgM, mutations in MYD88 and/or CD79B, loss of CDKN2A, or survival. In conclusion, PCFCL-LC uniformly classified as GCB, while PCDLBCL-LT classified along the COO spectrum of DLBCL-NOS using the Hans and Lymph2Cx algorithms. In contrast to DLBCL-NOS, the clinical relevance of COO classification in CLBCL using these algorithms has limitations and cannot be used as an alternative for the current multiparameter approach in differentiation of PCDLBCL-LT and PCFCL-LC.


Leukemia ◽  
2003 ◽  
Vol 18 (3) ◽  
pp. 589-596 ◽  
Author(s):  
J J F Muris ◽  
C J L M Meijer ◽  
S A G M Cillessen ◽  
W Vos ◽  
J A Kummer ◽  
...  

Apmis ◽  
2009 ◽  
Vol 117 (2) ◽  
pp. 87-94 ◽  
Author(s):  
SUN MI LEE ◽  
EUI JIN LEE ◽  
YOUNG-HYEH KO ◽  
SUG HYUNG LEE ◽  
LEESO MAENG ◽  
...  

2005 ◽  
Vol 40 (1) ◽  
pp. 15
Author(s):  
Sang-Eun Park ◽  
Su-Jin Park ◽  
Nam-Suk Park ◽  
Jae-Min Chun ◽  
Nam-Whan Park ◽  
...  

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 344-344 ◽  
Author(s):  
Andreas Rosenwald ◽  
Laurie H Sehn ◽  
Delphine Maucort-Boulch

Abstract Introduction MYC-rearrangement (MYC-R) occurs in approximately 10-15% of diffuse large B-cell lymphomas (DLBCL) and several studies suggest an inferior progression free (PFS) as well as overall survival (OS) compared to DLBCL without MYC-R. However, the prognostic significance of MYC single-hit (MYC-SH), MYC double/triple-hit (MYC and BCL2 and/or BCL6 translocation; MYC-DH/TH) in the context of the MYC translocation partner (MYC-IG versus MYC-non-IG) is less clear due to relatively small sample sizes in prior studies. The Lunenburg Lymphoma Biomarker Consortium (LLBC) set out to address these questions in a large number of DLBCL treated uniformly with rituximab (R)-CHOP- or R-CHOP-like chemotherapy. Methods Relevant clinical data (IPI factors, PFS, OS) from patients with aggressive B-cell lymphomas with confirmed DLBCL morphology derived from registry cohorts (Canada: British Columbia Cancer, UK: Leeds/HMRN, Barts, USA: Stanford) and prospective clinical trials (Germany: RICOVER, MegaCHOEP, France: LNH01-5B and LNH03-B, HOVON: HO 46 and 84) were pooled in the LLBC database (n=5118). Interphase FISH analysis (mostly on tissue microarrays) was used to determine the MYC-, BCL2- and BCL6-rearrangement status. All DLBCL with available tissue underwent break-apart testing for MYC (Vysis, LSI, Abbott). Identified MYC-R cases were subjected to FISH break-apart testing for the BCL2- and BCL6 loci as well as to MYC/IGH fusion testing and, if negative, to MYC/IGK and MYC/IGL testing to allow designation of the final MYC-R status (MYC-IG versus MYC-non-IG). Information on the cell of origin (COO) was generated using immunohistochemistry (Hans classifier) and/or gene expression based methods. Survival probabilities were estimated using the Kaplan Meier method and survival curves were compared with the log-rank test. The effects of variables of interest were estimated using univariate and multivariate Cox models stratified on the variable 'cohort' and 'trial'. Results 2380 DLBCL patients with full data on PFS, OS, IPI factors and MYC FISH results were available for analysis. 263 DLBCL cases (11%) had MYC-R which was associated with inferior PFS and OS compared to DLBCL patients without MYC-R (59% versus 72% OS at five years; log-rank <0.001; 56% versus 64% PFS at five years; log-rank <0.002). This effect was observed in both COO subgroups (GCB and non GCB). Out of 163 MYC-R patients with complete FISH data, 40 were MYC-SH with an IG partner (24.5%) and 17 (10.5%) with a non-IG partner. 53 patients had a MYC DH/TH constellation with an IG partner (32.5%) and 53 patients (32.5%) with a non-IG partner. The MYC-DH/TH group with an IG partner had the worst OS at 24 months: (50.9% compared to 76.4% for the remaining MYC-R DLBCL patients and to 82.4% for patients without MYC-R) (fig1). Similar results were obtained for PFS. In the MYC-DH group, there were no differences in OS and PFS between MYC/BCL2 and MYC/BCL6 'double hits'. Multivariate Cox models adjusting for the IPI and including a time-dependent effect showed, that the impact on outcomes was mainly seen in the first 24 months post therapy (hazard ratio (HR) of 2 [1.59-2.53] for MYC-R DLBCL patients compared to patients without MYC-R and a HR of 3.12 [2.09-4.64] for MYC-DH/TH tumors in which MYC is translocated to IG). In contrast, in MYC-R patients including MYC-SH and MYC-DH/TH without an IG partner, the HR was lower at 1.5 [1.01-2.24]. Conclusion This study by the LLBC in a very large cohort of DLBCL patients treated with R-CHOP or R-CHOP-like therapy confirms previous reports on the negative prognostic impact of an underlying MYC-translocation for both PFS and OS. This impact is predominantly observed in the first two years post therapy. Further, the large sample size extends previous observations that the partner gene of MYC (IG versus non-IG) also has prognostic impact. MYC-DH/TH DLBCL with an IG partner gene have the worst OS and PFS, while impact is moderate in other constellations (MYC-SH and MYC-DH/TH with a non-IG partner). Additionally, no differences between MYC/BCL2 and MYC/BCL6 'double hits' are seen in PFS and OS. Our results suggest that along with MYC testing in routine clinical practice, identification of the MYC partner gene (IG versus non-IG) is also warranted to identify further DLBCL subsets with poor outcomes which may have implications in the design and interpretation of future clinical trials. Figure 1. Figure 1. Disclosures Sehn: Merck: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Lundbeck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.


Sign in / Sign up

Export Citation Format

Share Document