Publications by authors named "Mattias Berglund"

46 Publications

Prognostic impact of soluble CD163 in patients with diffuse large Bcell lymphoma.

Haematologica 2021 Mar 25. Epub 2021 Mar 25.

Research Program Unit, Applied Tumor Genomics, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, Helsinki.

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http://dx.doi.org/10.3324/haematol.2020.278182DOI Listing
March 2021

PD-L1 and IDO1 are potential targets for treatment in patients with primary diffuse large B-cell lymphoma of the CNS.

Acta Oncol 2021 Apr 12;60(4):531-538. Epub 2021 Feb 12.

Clinical and Experimental Pathology, Department of Immunology, Genetics and Pathology, Uppsala University and University Hospital, Uppsala, Sweden.

Background: Programmed cell death 1 (PD-1) and its ligands PD-L1 and PD-L2, as well as Indoleamine 2,3-deoxygenase (IDO1) can be expressed both by tumor and microenvironmental cells and are crucial for tumor immune escape. We aimed to evaluate the role of PD-1, its ligands and IDO1 in a cohort of patients with primary diffuse large B-cell lymphoma of the CNS (PCNSL).

Material And Methods: Tissue microarrays (TMAs) were constructed in 45 PCNSL cases. RNA extraction from whole tissue sections and RNA sequencing were successfully performed in 33 cases. Immunohistochemical stainings for PD-1, PD-L1/paired box protein 5 (PAX-5), PD-L2/PAX-5 and IDO1, and Epstein-Barr virus encoding RNA (EBER) hybridization were analyzed.

Results: High proportions of PD-L1 and PD-L2 positive tumor cells were observed in 11% and 9% of cases, respectively. High proportions of PD-L1 and PD-L2 positive leukocytes were observed in 55% and 51% of cases, respectively. RNA sequencing revealed that gene expression of was high in patients with high proportion of PD-L1 positive leukocytes ( = .01). Protein expression of IDO1 in leukocytes was detected in 14/45 cases, in 79% of these cases a high proportion of PD-L1 positive leukocytes was observed. Gene expression of was high in EBER-positive cases ( = .0009) and protein expression of IDO1 was detected in five of six EBER-positive cases.

Conclusion: Our study shows a significant association between gene and protein expression of IDO1 and protein expression of PD-L1 in the tumor microenvironment of PCNSL, possibly of importance for prediction of response to immunotherapies.
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http://dx.doi.org/10.1080/0284186X.2021.1881161DOI Listing
April 2021

Diffuse Large B Cell Lymphoma Cell Line U-2946: Model for MCL1 Inhibitor Testing.

PLoS One 2016 1;11(12):e0167599. Epub 2016 Dec 1.

Department of Immunology, Genetics and Pathology, Uppsala University and Uppsala University Hospital, Uppsala, Sweden.

Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma worldwide. We describe the establishment and molecular characteristics of the DLBCL cell line U-2946. This cell line was derived from a 52-year-old male with DLBCL. U-2946 cells carried the chromosomal translocation t(8;14) and strongly expressed MYC, but not the mature B-cell lymphoma associated oncogenes BCL2 and BCL6. Instead, U-2946 cells expressed the antiapoptotic BCL2 family member MCL1 which was highly amplified genomically (14n). MCL1 amplification is recurrent in DLBCL, especially in the activated B cell (ABC) variant. Results of microarray expression cluster analysis placed U-2946 together with ABC-, but apart from germinal center (GC)-type DLBCL cell lines. The 1q21.3 region including MCL1 was focally coamplified with a short region of 17p11.2 (also present at 14n). The MCL1 inhibitor A-1210477 triggered apoptosis in U-2946 (MCL1pos/BCL2neg) cells. In contrast to BCL2pos DLBCL cell lines, U-2946 did not respond to the BCL2 inhibitor ABT-263. In conclusion, the novel characteristics of cell line U-2946 renders it a unique model system to test the function of small molecule inhibitors, especially when constructing a panel of DLBCL cell lines expressing broad combinations of antiapoptotic BCL2-family members.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167599PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132233PMC
July 2017

Core needle biopsies for the diagnosis of diffuse large B-cell lymphoma - a great concern for research.

Acta Oncol 2017 Jan 31;56(1):106-109. Epub 2016 Oct 31.

a Department of Immunology, Genetics and Pathology, Unit of Pathology , Uppsala University and Uppsala University Hospital , Uppsala , Sweden.

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http://dx.doi.org/10.1080/0284186X.2016.1245863DOI Listing
January 2017

A population-based study of cellular markers in R-CHOP treated diffuse large B-cell lymphoma patients.

Acta Oncol 2016 Sep - Oct;55(9-10):1126-1131. Epub 2016 Aug 23.

a Department of Immunology, Genetics and Pathology, Unit of Pathology , Uppsala University and Uppsala University Hospital, Uppsala, Sweden.

Aim: To determine the prognostic significance of co-expression of MYC, BCL-2 and BCL-6 proteins in combination with other biomarkers and clinical characteristics within a population-based cohort of diffuse large B-cell lymphoma (DLBCL) patients uniformly treated with R-CHOP.

Patients And Methods: The immunohistochemical (IHC) expression of CD10, BCL-2, BCL-6, MUM1, MYC, CD5, CD30, Ki-67 and p53 was evaluated in a retrospective, population-based study comprising 188 DLBCL patients treated with R-CHOP and diagnosed in Sweden between 2002 and 2012.

Results: Patients had a median age at diagnosis of 64 years (26-85 years) with a male:female ratio of 1.4:1. Approximately half (52%) of the patients presented with an International Prognostic Index (IPI) age adjusted (IPIaa) ≥ 2. Median follow-up time was 51 months (range 0.4-158) and the five-year lymphoma-specific survival (LSS) was 76%, five-year overall survival (OS) was 65% and five-year progression-free survival (PFS) was 61%. A high Ki-67 value was found in 59% of patients, while p53 overexpression was detected in 12% of patients and MYC, BCL-2 and BCL-6 expression were detected in 42%, 55% and 74% of patients, respectively. IPIaa ≥2 (p = 0.002), Ki-67 ≥ 70% (p = 0.04) and p53 overexpression ≥50% (p = 0.02) were associated with inferior LSS and OS. Co-expression of both MYC (>40%) and BCL-2 (>70%) proteins was detected in 27% of patients and correlated with a significantly inferior LSS (p = 0.0002), OS (p = 0.009) and PFS (p = 0.03). In addition, triple expression of MYC, BCL-2 and BCL-6, also correlated with a significantly inferior LSS (p = 0.02).

Conclusion: Concurrent expression of MYC and BCL-2 proteins, as detected by IHC, was strongly associated with an inferior survival in DLBCL patients treated with R-CHOP. Other markers affecting survival were triple expression of MYC, BCL-2 and BCL-6, IPIaa, high Ki-67 and p53 overexpression.
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http://dx.doi.org/10.1080/0284186X.2016.1189093DOI Listing
January 2018

Estrogen receptor β1 in diffuse large B-cell lymphoma growth and as a prognostic biomarker.

Leuk Lymphoma 2017 02 29;58(2):418-427. Epub 2016 Jun 29.

a Department of Biosciences and Nutrition , Karolinska Institutet , Huddinge , Sweden.

Diffuse large B-cell lymphoma (DLBCL) shows a higher incidence in males versus females. Epidemiological studies have shown that female gender is a favorable prognostic factor, which may be explained by estrogens. Here we show that when grafting human DLBCL cells to immunocompromised mice, tumor growth in males is faster. When treating mice grafted with either germinal center or activated B-cell like DLBCL cells with the selective estrogen receptor β (ERβ) agonist diarylpropionitrile, tumor growth was significantly inhibited. Furthermore, nuclear ERβ1 expression analysis in primary DLBCL's by immunohistochemistry revealed expression in 89% of the cases. Nuclear ERβ1 expression was in a univariate and multivariate analysis, an independent prognostic factor for adverse progression-free survival in Rituximab-chemotherapy treated DLBCL (p = 0.02 and p = 0.04, respectively). These results suggest that estrogen signaling through ERβ1 is an interesting future therapeutic target for treatment of DLBCL, and that ERβ1 expression can be used as a prognostic marker.
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http://dx.doi.org/10.1080/10428194.2016.1193853DOI Listing
February 2017

Expression of possible targets for new proteasome inhibitors in diffuse large B-cell lymphoma.

Eur J Haematol 2017 Jan 12;98(1):52-56. Epub 2016 Jul 12.

Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.

Objectives: Investigating expression of possible targets for proteasome inhibitors in patients with diffuse large B-cell lymphoma (DLBCL) and correlating the findings to clinical parameters and outcome.

Methods: Tumour material from 92 patients with DLBCL treated with either R-CHOP like (n = 69) or CHOP like (n = 23) regimens were stained for possible targets of proteasome inhibitors.

Results: The primary target molecule of bortezomib, proteasome subunit beta, type 5 (PSMB5), was not detected in the tumour cells in any of the cases but showed an abundant expression in cells in the microenvironment. However, the deubiquitinases (DUBs) of the proteasome, the ubiquitin carboxyl-terminal hydrolase L5 (UCHL5) and the ubiquitin specific peptidase 14 (USP14), were detected in the cytoplasm of the tumour cells in 77% and 74% of the cases, respectively. The adhesion regulating molecule 1 (ADRM1) was detected in 98% of the cases. There was no correlation between the expression of any of the studied markers and clinical outcome or GC/non-GC phenotype.

Conclusions: We suggest that UCHL5 and/or USP14 should be further evaluated as new targets for proteasome inhibitors in DLBCL. The lack of expression of PSMB5 on the tumour cells might provide an explanation of the relatively poor results of bortezomib in DLBCL.
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http://dx.doi.org/10.1111/ejh.12784DOI Listing
January 2017

Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas.

Blood 2016 06 30;127(24):3026-34. Epub 2016 Mar 30.

Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden;

Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive types of B-cell lymphoma. Deregulation of proto-oncogene expression after a translocation, most notably to the immunoglobulin heavy-chain locus (IGH), is one of the hallmarks of DLBCL. Using whole-genome sequencing analysis, we have identified the PD-L1/PD-L2 locus as a recurrent translocation partner for IGH in DLBCL. PIM1 and TP63 were also identified as novel translocation partners for PD-L1/PD-L2 Fluorescence in situ hybridization was furthermore used to rapidly screen an expanded DLBCL cohort. Collectively, a subset of samples was found to be affected by gains (12%), amplifications (3%), and translocations (4%) of the PD-L1/PD-L2 locus. RNA sequencing data coupled with immunohistochemistry revealed that these cytogenetic alterations correlated with increased expression of PD-L1 but not of PD-L2 Moreover, cytogenetic alterations affecting the PD-L1/PD-L2 locus were more frequently observed in the non-germinal center B cell-like (non-GCB) subtype of DLBCL. These findings demonstrate the genetic basis of PD-L1 overexpression in DLBCL and suggest that treatments targeting the PD-1-PD-L1/PD-L2 axis might benefit DLBCL patients, especially those belonging to the more aggressive non-GCB subtype.
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http://dx.doi.org/10.1182/blood-2015-12-686550DOI Listing
June 2016

Picropodophyllin inhibits proliferation and survival of diffuse large B-cell lymphoma cells.

Med Oncol 2015 Jul 29;32(7):188. Epub 2015 May 29.

Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, 751 85, Uppsala, Sweden.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults. Although chemotherapy in combination with anti-CD20 antibodies results in a cure rate of 60-70 %, novel treatment approaches are warranted for the remaining patients. The insulin-like growth factor-1 receptor (IGF-1R) and its principal ligands IGF-1 and IGF-2 have been suggested to play pivotal roles in different cancers. However, in DLBCL the importance of this system is less well understood. To assess whether interference with IGF-1R-mediated signaling may represent a therapeutic option for this malignancy, we used a panel of eight DLBCL cell lines together with primary tumor cells derived from lymph nodes in four DLBCL patients. The cells were treated with the cyclolignan picropodophyllin (PPP), a small molecule compound initially described to selectively inhibit the IGF-1R. PPP dose-dependently inhibited proliferation/survival in all cell lines and primary cell preparations. In parallel experiments, the IGF-1R inhibitor NVP-AEW541 and the microtubule-destabilizing compounds podophyllotoxin (PPT) and colchicine were demonstrated to also inhibit growth of the cell lines. Linear regression analysis showed that the responses of the cell lines to PPP correlated with their responses to the microtubule inhibitors PPT and colchicine, but not with the response to NVP-AEW541 or the expression level of surface IGF-1R. Analysis of cell cycle phase distribution revealed that treatment with PPP for only 1 h induced a clear accumulation of cells in the G2/M-phase with a corresponding depletion of the G0/G1-phase. Interestingly, these cell cycle effects could be closely mimicked by using PPT or colchicine. Treatment with PPP led to increased apoptotic cell death in the SU-DHL-6 and U-2932 cell lines, whereas the DB and U-2940 did not undergo apoptosis. However, the DB cells were still killed by PPP, suggesting another mode of cell death for this cell line. The U-2940 cells responded to PPP mainly by inhibition of proliferation. Pretreatment of U-2932 or U-2940 cell lines with PPP at biologically active concentrations did not prevent ligand-induced phosphorylation of IGF-1R at Tyr1131/1136 or its downstream targets AKT and ERK1/2. In contrast, the IGF-1R inhibitor NVP-AEW541 clearly inhibited phosphorylation of IGF-1R and AKT, while ERK1/2 phosphorylation was less affected. Taken together, the inhibitory effects of PPP in DLBCL cells together with its low toxicity in vivo makes it a promising drug candidate in the treatment of this disease. However, we suggest that the primary target of PPP in these cells is not related to inhibition of IGF-1R phosphorylation.
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http://dx.doi.org/10.1007/s12032-015-0630-yDOI Listing
July 2015

Male gender is an adverse risk factor only in young patients with diffuse large B-cell lymphoma - a Swedish population-based study.

Acta Oncol 2015 Jun 6;54(6):924-32. Epub 2015 Apr 6.

Department of Radiology, Oncology, and Radiation Sciences, Uppsala University , Uppsala , Sweden.

Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas. Five clinical adverse risk factors are merged into the International Prognostic Index (IPI), which is the major tool for prognostication. In contrast to Hodgkin's lymphoma, gender is not considered as an adverse risk factor for DLBCL patients. As we clinically had observed a very good survival rate in young female patients we hypothesised that there was a gender difference in survival due to the hormonal status of the patient.

Material And Methods: We conducted a registry-based retrospective cohort study of all Swedish DLBCL patients diagnosed between 2000 and 2013, to evaluate the impact of gender for survival from DLBCL.

Results: In total, 7166 patients were included for further analysis. No survival difference was found between the genders when the entire population was analysed. However, analysis of 880 young patients of pre-menopausal age (i.e. 52 years) revealed that women had a longer survival compared to men of the same age group (p=0.007). This was not found for patients older than menopausal age. In a relative survival multifactorial model adjusted for stage, ECOG performance status, serum lactate dehydrogenase and two or more extranodal sites, male gender was found to be an adverse risk factor for patients younger than 52 years (RR 1.51, 95% CI 1.14-1.88), but not for older patients (RR 0.99, 95% CI 0.89-1.10).

Conclusion: This is one of the largest population-based studies of DLBCL presented to date. Most interestingly, we found male gender to be a significant adverse risk factor compared to fertile women whereas we found no survival differences between genders in the older sub-population.
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http://dx.doi.org/10.3109/0284186X.2015.1026455DOI Listing
June 2015

The MDM2 polymorphism SNP309 is associated with clinical characteristics and outcome in diffuse large B-cell lymphoma.

Eur J Haematol 2014 Dec 21;93(6):500-8. Epub 2014 Jun 21.

Department of Radiology, Oncology and Radiation Sciences, Section of Oncology, Uppsala University, Uppsala, Sweden.

Introduction: The murine double minute 2 (MDM2) gene encodes a regulatory protein of the p53 pathway. A single nucleotide polymorphism (T to G change) at position 309 (SNP309) in the promotor region of MDM2 affects the transcription activity of MDM2 and has been found to be a negative prognostic marker in several cancers.

Patients And Methods: In this study, the MDM2 SNP309 polymorphism was analysed in 201 patients with diffuse large B-cell lymphoma and analysed in relation to clinical characteristics and prognosis.

Results: Patients homozygous for SNP309T had a significantly longer overall survival, lymphoma-specific survival and disease-free survival (P = 0.002; 0.004 and 0.006 respectively) compared to patients carrying a G allele. The longer overall survival was seen in the subgroup of patients not treated with Rituximab, however, not for Rituximab-treated patients (P = 0.01 and 0.2 respectively). The group homozygous for the T allele also had lower age at diagnosis, a tendency towards lower aaIPI and a significantly lower proportion of patients with p53 aberrations compared to the group including at least one G allele. However, the survival differences persisted even after removal of cases with known p53 aberrations from the analysis.

Conclusion: Polymorphism in MDM2 SNP309 could be correlated to some clinical characteristics and for patients not treated with immunotherapy, a G allele was correlated to poor survival, whereas no survival differences were found for patients treated with Rituximab. Herewith, we provide additional information about Diffuse large B-cell Lymphoma (DLBCL) biology and highlight the importance of evaluation of molecular markers in relation to treatment.
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http://dx.doi.org/10.1111/ejh.12388DOI Listing
December 2014

Amplification of 2p as a genomic marker for transformation in lymphoma.

Genes Chromosomes Cancer 2014 Sep 15;53(9):750-68. Epub 2014 May 15.

Department of Oncology-Pathology, Karolinska Institutet, CCK Karolinska University Hospital, Solna, Sweden.

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 NFκΒ-pathway) compared with BCL11A, which indicates that the altered genes disrupting the NFκΒ 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 NFκΒ-pathways for the transformation from FL to DLBCL.
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http://dx.doi.org/10.1002/gcc.22184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369132PMC
September 2014

DNA repair genes are selectively mutated in diffuse large B cell lymphomas.

J Exp Med 2013 Aug 19;210(9):1729-42. Epub 2013 Aug 19.

Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Sweden.

DNA repair mechanisms are fundamental for B cell development, which relies on the somatic diversification of the immunoglobulin genes by V(D)J recombination, somatic hypermutation, and class switch recombination. Their failure is postulated to promote genomic instability and malignant transformation in B cells. By performing targeted sequencing of 73 key DNA repair genes in 29 B cell lymphoma samples, somatic and germline mutations were identified in various DNA repair pathways, mainly in diffuse large B cell lymphomas (DLBCLs). Mutations in mismatch repair genes (EXO1, MSH2, and MSH6) were associated with microsatellite instability, increased number of somatic insertions/deletions, and altered mutation signatures in tumors. Somatic mutations in nonhomologous end-joining (NHEJ) genes (DCLRE1C/ARTEMIS, PRKDC/DNA-PKcs, XRCC5/KU80, and XRCC6/KU70) were identified in four DLBCL tumors and cytogenetic analyses revealed that translocations involving the immunoglobulin-heavy chain locus occurred exclusively in NHEJ-mutated samples. The novel mutation targets, CHEK2 and PARP1, were further screened in expanded DLBCL cohorts, and somatic as well as novel and rare germline mutations were identified in 8 and 5% of analyzed tumors, respectively. By correlating defects in a subset of DNA damage response and repair genes with genomic instability events in tumors, we propose that these genes play a role in DLBCL lymphomagenesis.
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http://dx.doi.org/10.1084/jem.20122842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3754869PMC
August 2013

Coding variants at hexa-allelic amino acid 13 of HLA-DRB1 explain independent SNP associations with follicular lymphoma risk.

Am J Hum Genet 2013 Jul 20;93(1):167-72. Epub 2013 Jun 20.

Human Genetics, Genome Institute of Singapore, Agency for Science, Technology, and Research, Singapore 138672, Singapore.

Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 × 10⁻¹⁵). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9-6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 × 10⁻¹⁴). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis.
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http://dx.doi.org/10.1016/j.ajhg.2013.05.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3710749PMC
July 2013

Low expression of microRNA-129-5p predicts poor clinical outcome in diffuse large B cell lymphoma (DLBCL).

Int J Hematol 2013 Apr 5;97(4):465-71. Epub 2013 Mar 5.

Department of Radiology, Oncology, and Radiation Sciences, Uppsala University, Uppsala, Sweden.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of B cell lymphomas. MicroRNA expression provides a new and interesting tool for understanding the biology and clinical course of DLBCL. The present study presents microRNA-129-5p expression data from DLBCL patients treated with CHOP or R-CHOP. Patients with low microRNA-129-5p expression had a median survival of 23 months and a significantly shorter overall survival (P = 0.0042) compared to patients with high microRNA-129-5p expression, who had a median survival of 58 months. We also found that patients treated with R-CHOP only and displaying low microRNA-129-5p expression had a significantly shorter overall survival compared to patients with high microRNA-129-5p expression; all such patients were still alive at the time of last follow-up (P = 0.043). No significant difference was found among microRNA-129-5p expression in tumor tissue, the tissue surrounding the tumor, and normal controls. To our knowledge, this is the first report to show that the expression of microRNA-129-5p can affect the clinical outcome of DLBCL patients and that microRNA-129-5p may be involved in the biology of DLBCL development, although larger studies are necessary to confirm this. Further investigations may also help to elucidate the biological role of microRNA-129-5p in DLBCL.
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http://dx.doi.org/10.1007/s12185-013-1303-2DOI Listing
April 2013

High expression of microRNA-200c predicts poor clinical outcome in diffuse large B-cell lymphoma.

Oncol Rep 2013 Feb 10;29(2):720-4. Epub 2012 Dec 10.

Department of Radiology, Oncology and Radiation Sciences, Uppsala University, Uppsala, Sweden.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of B-cell lymphomas. A new and important tool for understanding the biology and clinical course of DLBCL is microRNA expression. This study presents microRNA-200c expression data from 61 DLBCL patients treated with CHOP or R-CHOP. Patients with high microRNA-200c expression had a median survival of 20.3 months and a significantly shorter overall survival (P=0.019) compared to patients with low microRNA-200c expression, who had a median survival of 35.8 months. We also found that patients treated with R-CHOP only and displaying high microRNA-200c expression had a significantly shorter overall survival compared to patients with low microRNA-200c expression, where all patients were still alive at the time of the last follow-up (P=0.0036). Lastly, we found that patients with high microRNA-200c expression had a significantly shorter time from initial diagnosis to the first relapse compared to patients with low microRNA-200c expression (P=0.0001). To our knowledge, this is the first study showing that the expression of microRNA-200c affects the clinical outcome of DLBCL patients, and that microRNA-200c is involved in the biology of DLBCL development, although larger studies are necessary to confirm this. Further investigations may also help to elucidate the biological role of microRNA-200c in DLBCL.
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http://dx.doi.org/10.3892/or.2012.2173DOI Listing
February 2013

Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis.

J Exp Med 2012 Feb 6;209(2):291-305. Epub 2012 Feb 6.

Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, SE-14186 Stockholm, Sweden.

Cernunnos is involved in the nonhomologous end-joining (NHEJ) process during DNA double-strand break (DSB) repair. Here, we studied immunoglobulin (Ig) class switch recombination (CSR), a physiological process which relies on proper repair of the DSBs, in B cells from Cernunnos-deficient patients. The pattern of in vivo generated CSR junctions is altered in these cells, with unusually long microhomologies and a lack of direct end-joining. The CSR junctions from Cernunnos-deficient patients largely resemble those from patients lacking DNA ligase IV, Artemis, or ATM, suggesting that these factors are involved in the same end-joining pathway during CSR. By screening 269 mature B cell lymphoma biopsies, we also identified a somatic missense Cernunnos mutation in a diffuse large B cell lymphoma sample. This mutation has a dominant-negative effect on joining of a subset of DNA ends in an in vitro NHEJ assay. Translocations involving both Ig heavy chain loci and clonal-like, dynamic IgA switching activities were observed in this tumor. Collectively, our results suggest a link between defects in the Cernunnos-dependent NHEJ pathway and aberrant CSR or switch translocations during the development of B cell malignancies.
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http://dx.doi.org/10.1084/jem.20110325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280866PMC
February 2012

Superficial dose distribution in breast for tangential radiation treatment, Monte Carlo evaluation of Eclipse algorithms in case of phantom and patient geometries.

Radiother Oncol 2012 Jan 7;102(1):102-7. Epub 2011 Jul 7.

Department of Medical Physics and Biomedical Engineering, Gothenburg, Sweden.

Purpose: The aim of this study is to examine experimentally and by the Monte Carlo method the accuracy of the Eclipse Pencil Beam Convolution (PBC) and Analytical Anisotropic Algorithm (AAA) algorithms in the superficial region (0-2 cm) of the breast for tangential photon beams in a phantom case as well as in a number of patient geometries. The aim is also to identify differences in how the patient computer tomography data are handled by the treatment planning system and in the Monte Carlo simulations in order to reduce influences of these effects on the evaluation.

Materials And Methods: Measurements by thermoluminescent dosimeters and gafchromic film are performed for six MV tangential irradiation of the cylindrical solid water phantom. Tangential treatment of seven patients is investigated considering open beams. Dose distributions are obtained by the Eclipse PBC and AAA algorithms. Monte Carlo calculations are carried out by BEAMnrc/DOSXYZnrc code package. Calculations are performed with a calculation grid of 1.25×1.25×5 mm(3) for PBC and 2×2×5 mm(3) for AAA and Monte Carlo, respectively. Dose comparison is performed in both dose and spatial domains by the normalized dose difference method.

Results: Experimental profiles from the surface toward the geometrical center of the cylindrical phantom are obtained at the beam entrance and exit as well as laterally. Full dose is received beyond 2 mm in the lateral superficial region and beyond 7 mm at the beam entrance. Good agreement between experimental, Monte Carlo and AAA data is obtained, whereas PBC is seen to underestimate the entrance dose the first 3-4 mm and the lateral dose by more than 5% up to 8 mm depth. In the patient cases considered, AAA and Monte Carlo show agreement within 3% dose and 4 mm spatial tolerance. PBC systematically underestimates the dose at the breast apex. The dimensions of region out of tolerance vary with the local breast shape. Different interpretations of patient boundaries in Monte Carlo and the Eclipse are found to influence the evaluation. Computer tomography marker wire may introduce local disturbance effects on the comparison as well. These factors are not related to the accuracy of the calculation algorithms and their effect is taken into account in the evaluation.

Conclusions: The accuracy of AAA in the case of the solid water phantom is comparable with that of the Monte Carlo method. The AAA-Monte Carlo differences in the patient cases considered are within 3%, 4 mm tolerance. The PBC algorithm does not give equivalent results. In the phantom case, PBC underestimates the lateral dose by more than 5% up to 8 mm depth. The PBC-Monte Carlo differences in the patient cases are outside the tolerance at the breast apex. The dimension of region varies with the breast shape being typically 8-10 mm long and 6-8 mm deep.
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http://dx.doi.org/10.1016/j.radonc.2011.06.021DOI Listing
January 2012

Quantitative evaluation of p16(INK4a) promoter methylation using pyrosequencing in de novo diffuse large B-cell lymphoma.

Leuk Res 2011 Apr 29;35(4):438-43. Epub 2010 Oct 29.

Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden.

The p16(INK4a) tumor suppressor gene can be inactivated by a variety of events including promoter hypermethylation. In diffuse large B-cell lymphoma (DLBCL), p16(INK4a) methylation has been associated with advanced disease stage and higher IPI. The prognostic impact of p16(INK4a) methylation in DLBCL remains unclear; however, it has been suggested to correlate with inferior outcome. To further investigate the clinical impact of p16(INK4a) methylation in DLBCL, promoter methylation of this gene was assessed quantitatively by pyrosequencing. Forty-two of 113 (37%) DLBCL patients with methylation level above 5% were categorized as methylated and subsequently divided into low, intermediate and high methylation categories. Overall, no association was shown between the extent of p16(INK4a) methylation and patients' clinical characteristics, except disease stage (P=0.049). Moreover, we could not reveal any impact of p16(INK4a) methylation on lymphoma-specific survival. Although >25% of p16(INK4a) methylation correlated with a better progression-free survival (P=0.048) in patients <65 years old, the significance of this finding, if any, needs to be further investigated. In conclusion, our finding questions the role of p16(INK4a) promoter methylation as a negative prognostic factor in DLBCL.
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http://dx.doi.org/10.1016/j.leukres.2010.10.001DOI Listing
April 2011

Does temperature regime govern the establishment of Heterobasidion annosum in Scandinavia?

Int J Biometeorol 2011 May 4;55(3):275-84. Epub 2010 Jun 4.

Southern Swedish Forest Research Centre, Swedish University of Agricultural Sciences, Alnarp, Sweden.

We explored the reasons underlying the biogeographic distribution patterns of the economically important, wood-rotting basidiomycete Heterobasidion annosum in Sweden. Despite the commonness of suitable host trees, Heterobasidion annosum has not been recorded in the north of Sweden, whereas its relative, H. parviporum, is present throughout the country. To test the hypothesis that H. annosum has not spread to the north because of the effect of climate, mainly differences in the general temperature regime, we inoculated Norway spruce stumps and standing trees with H. annosum and H. parviporum at six field sites, three in the south and three in the north of Sweden. Three strains of both species were used in random combinations, so that each selected stump and tree was inoculated with both species at the same time. At 2 and 10 months after the inoculations, we compared the frequencies of detection of H. annosum and H. parviporum colonies at different distances from inoculation points in the stumps and in trees. The H. annosum colonies were detected only infrequently on disks cut from the inoculated stumps (0-4% of re-isolations) in both areas, whereas H. parviporum was detected much more frequently (26-47% of re-isolations). In standing trees, colonies belonging to H. annosum could be detected up to 210 cm (south) and 80 cm (north) and those belonging to H. parviporum up to 210 cm (south) and 140 cm (north) above the inoculation points. Our results suggest that difference in temperature regime does not provide an explanation for the distribution limit of H. annosum.
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http://dx.doi.org/10.1007/s00484-010-0333-1DOI Listing
May 2011

Identification of uniquely expressed transcription factors in highly purified B-cell lymphoma samples.

Am J Hematol 2010 Jun;85(6):418-25

Department of Immunotechnology, Lund University, Sweden.

Transcription factors (TFs) are critical for B-cell differentiation, affecting gene expression both by repression and transcriptional activation. Still, this information is not used for classification of B-cell lymphomas (BCLs). Traditionally, BCLs are diagnosed based on a phenotypic resemblance to normal B-cells; assessed by immunohistochemistry or flow cytometry, by using a handful of phenotypic markers. In the last decade, diagnostic and prognostic evaluation has been facilitated by global gene expression profiling (GEP), providing a new powerful means for the classification, prediction of survival, and response to treatment of lymphomas. However, most GEP studies have typically been performed on whole tissue samples, containing varying degrees of tumor cell content, which results in uncertainties in data analysis. In this study, global GEP analyses were performed on highly purified, flow-cytometry sorted tumor-cells from eight subgroups of BCLs. This enabled identification of TFs that can be uniquely associated to the tumor cells of chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), hairy cell leukemia (HCL), and mantle cell lymphoma (MCL). The identified transcription factors influence both the global and specific gene expression of the BCLs and have possible implications for diagnosis and treatment.
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http://dx.doi.org/10.1002/ajh.21701DOI Listing
June 2010

Identification of molecular targets associated with transformed diffuse large B cell lymphoma using highly purified tumor cells.

Am J Hematol 2009 Dec;84(12):803-8

Department of Immunotechnology, Lund University, Lund, Sweden.

Follicular lymphoma (FL) frequently transforms into the more aggressive diffuse large B cell lymphoma (DLBCL-tr), but no protein biomarkers have been identified for predictive or early diagnosis. Gene expression analyses have identified genes changing on transformation but have failed to be reproducible in different studies, reflecting the heterogeneity within the tumor tissue and between tumor samples. Gene expression analyses on Affymetrix Human Genome U133 Plus 2.0 arrays were performed, using flow cytometry sorted tumor cells derived from FL and transformed DLBCL. To identify molecular targets associated with the transformation, subsequent immunohistochemistry (IHC) analyses of the corresponding proteins were performed. Using highly purified cells, this study identified 163 genes, which were significantly deregulated during the transformation in a majority of cases. Among the upregulated transcripts, 13 genes were selected for validation using IHC, based on the availability of commercial antibodies, and galectin-3 and NEK2 proteins specifically identify DLBCL-tr, when compared with FL. We demonstrate that by purifying tumor cells through cell sorting, thereby reducing the heterogeneity due to infiltrating cells, it was possible to identify distinct differences between tumor entities rather than variations due to cellular composition. Galectin-3 and NEK2 both identified a subgroup of DLBCL-tr, and the function of these protein markers also suggests a biological role in the transformation process.
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http://dx.doi.org/10.1002/ajh.21549DOI Listing
December 2009

TP53 mutations predict for poor survival in de novo diffuse large B-cell lymphoma of germinal center subtype.

Leuk Res 2009 Jan 15;33(1):60-6. Epub 2008 Aug 15.

Department of Oncology, Radiology and Clinical Immunology, Uppsala University, Uppsala, Sweden.

Presence of TP53 mutations has been associated with poor prognosis in diffuse large B-cell lymphoma (DLBCL), although this has remained controversial. The TP53 codon 72 polymorphism has shown negative impact on cancer survival, but this has not been analyzed in DLBCL. Furthermore, the MDM2 SNP309 has been associated with earlier age of onset in DLBCL. Here, we investigated the clinical impact of TP53 mutations, MDM2 SNP309 and TP53 codon 72 polymorphisms on survival in DLBCL of germinal center (GC) and non-GC subtypes. Thirteen of the 102 (12.7%) patients displayed TP53 mutations. Overall, TP53 mutations had a significant effect on lymphoma-specific survival (LSS, P=0.009) and progression-free survival (PFS, P=0.028). In particular, inferior survival was observed in TP53-mutated DLBCLs of GC subtype (LSS, P=0.002 and PFS, P=0.006). Neither MDM2 SNP309 nor the TP53 codon 72 polymorphism had an impact on age of onset or survival. Altogether, our data suggests that TP53 mutations are associated with poor outcome in GC-DLBCL patients.
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http://dx.doi.org/10.1016/j.leukres.2008.06.022DOI Listing
January 2009

Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma.

Br J Haematol 2008 May;141(4):423-32

Department of Oncology, Lund University Hospital, Lund, Sweden.

In order to identify genes associated with primary chemotherapy-resistance, gene expression profiles (GEP) in tumour tissue from 37 patients with de novo diffuse large B-cell lymphoma (DLBCL), stage II-IV, either in continuous complete remission (n = 24) or with progressive disease during primary treatment (n = 13), were examined using spotted 55K oligonucleotide arrays. Immunohistochemistry was used for confirmation at the protein level. The top 86 genes that best discriminated between the two cohorts were chosen for further analysis. Only seven of 86 genes were overexpressed in the refractory cohort, e.g. RABGGTB and POLE, both potential targets for drug intervention. Seventy-nine of 86 genes were overexpressed in the cured cohort and mainly coded for proteins expressed in the tumour microenvironment, many of them involved in proteolytic activity and remodelling of extra cellular matrix. Furthermore, major histocompatibility complex class I molecules, CD3D and ICAM1 were overexpressed, indicating an enhanced immunological reaction. Immunohistochemistry confirmed the GEP results. The frequency of tumour infiltrating lymphocytes, macrophages, and reactive cells expressing ICAM-1, lysozyme, cathepsin D, urokinase plasminogen activator receptor, signal transducer and activator of transcription 1, and galectin-3 was higher in the cured cohort. These findings indicate that a reactive microenvironment has an impact on the outcome of chemotherapy in DLBCL.
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http://dx.doi.org/10.1111/j.1365-2141.2008.07037.xDOI Listing
May 2008

Characterization of 6q deletions in mature B cell lymphomas and childhood acute lymphoblastic leukemia.

Leuk Lymphoma 2008 Mar;49(3):477-87

Medical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.

The study was undertaken with the aim to outline deletion patterns involving the long arm of chromosome 6, a common abnormality in lymphoproliferative disorders. Using a chromosome 6 specific tile path array, 60 samples from in total 49 cases with mantle cell lymphoma (MCL), de novo diffuse large B-cell lymphoma (DLBCL), transformed DLBCL as well as preceding follicular lymphoma (FL), and childhood acute lymphoblastic leukemia (ALL), were characterized. Twenty-six of the studied cases, representing all diagnoses, showed a 6q deletion among which 85% involved a 3 Mb region in 6q21. The minimal deleted interval in 6q21 encompasses the FOXO3A, PRDM1 and HACE1 candidate genes. The PRDM1 gene was found homozygously deleted in a case of DLBCL. Moreover, in two DLBCL cases, an overlapping homozygous deletion was identified in 6q23.3 - 24.1, encompassing the TNFAIP3 gene among others. Taken together, we refined the deletion pattern within the long arm of chromosome 6 in four different types of hematological malignances, suggesting the location of tumor suppressor genes involved in the tumor progression.
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http://dx.doi.org/10.1080/10428190701817282DOI Listing
March 2008