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| 2. |
- Kwiecinska, Anna, et al.
(författare)
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Amplification of 2p as a Genomic Marker for Transformation in Lymphoma
- 2014
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 53:9, s. 750-768
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Tidskriftsartikel (refereegranskat)abstract
- To outline further genetic mechanisms of transformation from follicular lymphoma (FL) to diffuse large B-cell lymphoma (DLBCL), we have performed whole genome array-CGH in 81 tumors from 60 patients [29 de novo DLBCL (dnDLBCL), 31 transformed DLBCL (tDLBCL), and 21 antecedent FL]. In 15 patients, paired tumor samples (primary FL and a subsequent tDLBCL) were available, among which three possessed more than two subsequent tumors, allowing us to follow specific genetic alterations acquired before, during, and after the transformation. Gain of 2p15-16.1 encompassing, among others, the REL, BCL11A, USP34, COMMD1, and OTX1 genes was found to be more common in the tDLBCL compared with dnDLBCL (P < 0.001). Furthermore, a high-level amplification of 2p15-16.1 was also detected in the FL stage prior to transformation, indicating its importance during the transformation event. Quantitative real-time PCR showed a higher level of amplification of REL, USP34, and COMMD1 (all involved in the NF kappa B-pathway) compared with BCL11A, which indicates that the altered genes disrupting the NF kappa B pathway may be the driver genes of transformation rather than the previously suggested BCL11A. Moreover, a 17q21.33 amplification was exclusively found in tDLBCL, never in FL (P < 0.04) or dnDLBCL, indicating an upregulation of genes of importance during the later phase of transformation. Taken together, our study demonstrates potential genomic markers for disease progression to clinically more aggressive forms. We also confirm the importance of the TP53-, CDKN2A-, and NF kappa B-pathways for the transformation from FL to DLBCL.
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| 3. |
- Kwiecińska, Anna, et al.
(författare)
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Proteomic Profiling of Diffuse Large B-Cell Lymphomas
- 2018
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Ingår i: Pathobiology. - : S. Karger AG. - 1015-2008 .- 1423-0291. ; 85:4, s. 211-219
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of this study was to identify differences in proteome profiles of diffuse large B-cell lymphoma (DLBCL) of nongerminal center (non-GC) versus GC type in the search for new markers and drug targets. Methods: Six DLBCL, with 3 repeats for each, were used for the initial study by proteomics: 3 non-GC and 3 GC DLBCL cases. For immunohistochemistry, tissue microarrays were made from 31 DLBCL samples: 16 non-GC de novo lymphomas and 15 GC cases (11 transformed from follicular lymphomas and 4 de novo GC lymphomas). Proteome profiling was performed by two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. Results: Ninety-one proteins were found differentially expressed in non-GC compared to GC type. The Cytoscape tool was used for systemic analysis of proteomics data, revealing 19 subnetworks representing functions affected in non-GC versus GC types of DLBCL. Conclusion: A validation study of 3 selected proteins (BiP/Grp78, Hsp90, and cyclin B2) showed the enhanced expression in non-GC DLBCL, supporting the proteomics data.
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| 4. |
- Rodrigues, Joana M., et al.
(författare)
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p53 is associated with high-risk and pinpoints TP53 missense mutations in mantle cell lymphoma
- 2020
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Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 191:5, s. 796-805
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Tidskriftsartikel (refereegranskat)abstract
- Survival for patients diagnosed with mantle cell lymphoma (MCL) has improved drastically in recent years. However, patients carrying mutations in tumour protein p53 (TP53) do not benefit from modern chemotherapy-based treatments and have poor prognosis. Thus, there is a clinical need to identify missense mutations through routine analysis to enable patient stratification. Sequencing is not widely implemented in clinical practice for MCL, and immunohistochemistry (IHC) is a feasible alternative to identify high-risk patients. The aim of the present study was to investigate the accuracy of p53 as a tool to identify patients with TP53 missense mutations and the prognostic impact of overexpression and mutations in a Swedish population-based cohort. In total, 317 cases were investigated using IHC and 255 cases were sequenced, enabling analysis of p53 and TP53 status among 137 cases divided over the two-cohort investigated. The accuracy of predicting missense mutations from protein expression was 82%, with sensitivity at 82% and specificity at 100% in paired samples. We further show the impact of p53 expression and TP53 mutations on survival (hazard ratio of 3·1 in univariate analysis for both), and the association to risk factors, such as high MCL International Prognostic Index, blastoid morphology and proliferation, in a population-based setting.
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| 5. |
- Rodrigues, Joana M., et al.
(författare)
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p53 is associated with high-risk and pinpointsTP53missense mutations in mantle cell lymphoma
- 2020
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Ingår i: British Journal of Haematology. - : WILEY. - 0007-1048 .- 1365-2141. ; 191:5, s. 796-805
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Tidskriftsartikel (refereegranskat)abstract
- Survival for patients diagnosed with mantle cell lymphoma (MCL) has improved drastically in recent years. However, patients carrying mutations in tumour protein p53 (TP53) do not benefit from modern chemotherapy-based treatments and have poor prognosis. Thus, there is a clinical need to identify missense mutations through routine analysis to enable patient stratification. Sequencing is not widely implemented in clinical practice for MCL, and immunohistochemistry (IHC) is a feasible alternative to identify high-risk patients. The aim of the present study was to investigate the accuracy of p53 as a tool to identify patients withTP53missense mutations and the prognostic impact of overexpression and mutations in a Swedish population-based cohort. In total, 317 cases were investigated using IHC and 255 cases were sequenced, enabling analysis of p53 andTP53status among 137 cases divided over the two-cohort investigated. The accuracy of predicting missense mutations from protein expression was 82%, with sensitivity at 82% and specificity at 100% in paired samples. We further show the impact of p53 expression andTP53mutations on survival (hazard ratio of 3 center dot 1 in univariate analysis for both), and the association to risk factors, such as high MCL International Prognostic Index, blastoid morphology and proliferation, in a population-based setting.
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| 6. |
- Adam, Makka, et al.
(författare)
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Clinical characteristics and histopathological patterns of hodgkin lymphoma and treatment outcomes at a tertiary cancer center in ethiopia
- 2021
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Ingår i: JCO Global Oncology. - 2687-8941. ; 7, s. 277-288
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE In developing countries, Hodgkin lymphoma (HL) affects the young population. In Ethiopia, nearly 70% of the population are, 35 years of age. Therefore, this study aimed to elucidate the age distribution, histopathologic patterns, clinical characteristics and treatment outcomes of HL in Ethiopia. MATERIALS AND METHODS Data from clinical records of 133 consecutive patients with HL between 2014 and 2019 were reviewed and collected. Formalin-fixed paraffin-embedded tissue blocks of HL cases were collected and used for subtype classification. RESULTS A total of 68.4% (91) of the patients were male; male-to-female ratio was 2.2:1. The median age was 22 years. The age distribution was 57.1% (76), 30.8% (41), and 2.3% (3) for the age groups (10-29), (30-59), and (60-69) years, respectively. Thirteen percent (12) were associated with HIV. The majority of the cases, 50.4% (67), were of the mixed-cellularity (MCCHL) subtypes and 30% (40) nodular-sclerosis (NSCCHL). Most HIV-associated cases (60%, 6) were of the MCHL subtype. The 4-year overall survival (OS) was 83.1%. The 4-year OS of early-stage patients was 100% and advanced-stage patients with low-risk (International Prognostic Score [IPS] ≤ 2) and high-risk (IPS ≥ 3) were 94.1% and 62.9%, respectively. All patients who received combined-therapy survived, whereas those who received doxorubicin, bleomycin, vinblastine, and dacarbazine only showed a 4-year OS rate of 77.9%. CONCLUSION HL affects the youngest and most productive population in Ethiopia. The treatment outcome is favorable in both HIV-associated and non–HIV-associated HL. However, the study population was likely a highly selected group as the majority of the Ethiopian population do not have access to specialized care.
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| 7. |
- Adam, Makka, et al.
(författare)
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Evidence for distinct mechanisms of immune suppression in EBV-positive and EBV-negative Hodgkin lymphoma
- 2023
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Ingår i: Journal of Clinical and Experimental Hematopathology. - 1346-4280. ; 63:4, s. 230-239
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Tidskriftsartikel (refereegranskat)abstract
- Epstein Barr Virus (EBV) has been recognized for its ability to transform B lymphocytes and for its association with different types of cancers including Hodgkin lymphoma. In addition, EBV may also modulate the microenvironment of HL. In this study, we aimed to investigate the prevalence of EBV among HL cases in Ethiopia and to assess the tissue cellular composition of EBV-related and EBV-unrelated cases. We constructed a tissue microarray (TMA) of 126 consecutive cases of classical HL (CHL) and nodular lymphocyte predominant HL (NLPHL) from a tertiary cancer centre, Tikur Anbessa Hospital, Addis Ababa, Ethiopia, and evaluated a panel of immunohistochemical markers. The quantification of immune cells was performed using HALO 2.3, a platform for image analysis from Indica Lab Inc. A total of 77/126 (61.1%) of HL cases expressed LMP1/EBER. Infiltration of CD8+, T-bet+ and FoxP3+ cells was higher in the microenvironment of EBV-related CHL, with P values of <0.001, <0.001 and <0.016, respectively. In contrast, the expression of PD1 was higher in the microenvironment of EBV-unrelated CHL cases (P < 0.001). Unlike in Western countries, the majority of HL cases in Ethiopia were associated with EBV. As FoxP3+ and PD1-expressing cells are thought to participate in down regulation of the immune response by different mecha-nisms, this finding highlights the previously unrecognized possibility that distinct immunosuppressive mechanisms may be ongoing within EBV positive and negative HL types. This may have important prognostic and therapeutic implications.
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| 8. |
- Kwiecińska, Anna
(författare)
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Characterisation of molecular alterations in diffuse large b-cell lymphoma with respect to transformation, progression and prognostic markers
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma type, and comprises nearly 500 newly diagnosed cases in Sweden every year. DLBCL is a group of aggressive lymphomas that are extremely heterogeneous and differ in morphology, immunophenotype, molecular and clinical features as well as in response to therapy. The transformation of low malignant lymphoma, most commonly follicular lymphoma (FL), to DLBCL is associated with a progressive disease and poor prognosis. The overall aim of this thesis was to identify the genetic events underlying the progression and transformation of indolent FL to aggressive DLBCL and to outline molecular alterations distinguishing DLBCL with germinal center (GC) and non-GC phenotype. In search for novel markers in lymphoma, we have investigated an anti-apoptotic protein, HS-associated protein X-1 (HAX-1), at the protein and transcript level in malignant lymphomas (paper I). We found high levels of HAX-1 mRNA and protein expression in Bcell lymphomas. We also identified a positive association between proliferation (Ki67) and HAX-1 expression, as well as an inverse correlation between Bcl-2 and HAX-1 demonstrated on a transcript and protein level in FL, which indicates the potential role of HAX-1 as a Bcl-2 homolog. In papers II and III we studied paired tumours of FL and its transformed DLBCL (tDLBCL) counterparts and compared with de novo DLBCL (dnDLBCL) using arraycomparative genome hybridisation (array-CGH) in order to outline genetic alteration of importance for the transformation process. We identified a gain of 2p15-16.1 as a potential prognostic marker, and that this alteration may appear already in the FL prior to transformation. This chromosomal region encompasses, among others, genes involved in NF- κB pathway, such as REL, USP34, COMMD1, OTX1 and of known importance for B-cell development, such as BCL11A. We have also performed whole exome sequencing (WES) results in a smaller group of patients with consecutive lymphoma samples. A comparison with array-CGH data showed that these two methods complement and strengthen each other in pinpointing crucial genetic events. Furthermore, our studies revealed that clonal evolution of transformed tumours occurs according to the branching model. A number of mutations identified in the peri-transformation phases – defined as FL appearing prior and tDLBCL directly after transformation - affected genes involved in histone modifications, cell cycle, apoptosis, PI-3 kinase pathway, and Ras signalling pathway. In Paper IV we performed proteomic profiling of DLBCL subtypes i.e. non-GC and GC, and identified 91 proteins present exclusively in the non-GC type of DLBCL. We focused on two proteins of importance for the NF-κB pathway (BiP and Hsp90) as well as on Cyclin B2. We observed increased expression of these three proteins in DLBCL and also in non-GC vs GC type of DLBCL. These findings suggest a potential relevance of these proteins as prognostic markers and may lead to new treatment options.
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