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Prognostic Markers in Diffuse Large B-cell Lymphoma: How Bad can it be
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Diffuse large B-cell lymphoma (DLBCL), which is the most common type of lymphoma, is characterised by its aggressiveness and poor outcome without adequate treatment and also for its biological and clinical heterogeneity. It is therefore highly desirable to gain a more profound understanding of the underlying biology of the disease, as well as predictive factors for the guidance of treatment. The studies presented here attempt to gain an overall grasp on DLBCL, from the epidemiological level down to the genomic level.

The tumour microenvironment consists of both tumour cells and normal infiltrating cells in a delicate interplay. By assessing the number of infiltrating mast cells (MCs) in the microenvironment, a correlation between low numbers of MCs and poorer prognosis of DLBCL was found.

However, malignant cells are not only affected by environmental conditions but also by intrinsic factors, such as small non-coding microRNAs. A low expression level of microRNA-129 was found to correlate with poor survival of DLBCL and the finding remained significant even for rituximab-treated patients.

An even smaller intracellular genomic unit is one single nucleotide. The single nucleotide polymorphism 309 (SNP309) is a T to G change in the promotor region of MDM2, a regulatory protein in the p53 pathway, which results in increased transcription of MDM2 and thus decreased levels of p53. It was found that homozygous T allele patients had longer overall survival, as well as disease-specific survival and disease-free survival. However, treatment with rituximab eliminated the predictive value of the SNP309 polymorphism.

In the last project presented in this thesis we used epidemiological methods to analyse all DLBCL cases diagnosed 2000-2013 in Sweden. Here it was possible to categorically show that higher age is an adverse prognostic factor, and most importantly, this starts from a young age.

In conclusion, within this thesis I have applied different laboratory and analysis techniques to examine DLBCL biology in relation to the clinic. I have identified potential new prognostic markers, contributed to an enhanced understanding of DLBCL biology and described epidemiological data from one of the largest DLBCL cohorts ever presented. All of these aspects provide important information for a deeper understanding of the disease DLBCL. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 85 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 978
Keyword [en]
DLBCL, Survival, Mast cell, Microenvironment, MicroRNA, MDM2, Polymorphism, Age, Epidemiology
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
URN: urn:nbn:se:uu:diva-220010ISBN: 978-91-554-8896-3 (print)OAI: oai:DiVA.org:uu-220010DiVA: diva2:703812
Public defence
2014-04-26, Auditorium Minus Gustavianum, Akademigatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2014-04-01 Created: 2014-03-09 Last updated: 2014-04-29
List of papers
1. Mast cell infiltration is a favourable prognostic factor in diffuse large B-cell lymphoma
Open this publication in new window or tab >>Mast cell infiltration is a favourable prognostic factor in diffuse large B-cell lymphoma
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2007 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 138, no 1, 68-71 p.Article in journal (Refereed) Published
Abstract [en]

Previous studies indicate that the inflammatory response in diffuse large B-cell lymphomas (DLBCL) is important for the clinical outcome. Mast cells are key regulators in this response; we investigated whether the number of tryptase-positive mast cells is correlated with clinical outcome. Patients with many mast cells had a significantly better event-free survival (EFS) compared to those with few mast cells (P < 0.03 in both germinal centre (GC) and non-GC DLBCL. This supports the idea that the infiltration of mast cells is a reflection of the host inflammatory response and is related to a favourable outcome.

Keyword
Aged, Biological Markers/analysis, Cell Movement, Disease-Free Survival, Female, Humans, Immunohistochemistry, Lymphoma; Large B-Cell; Diffuse/*immunology, Male, Mast Cells/enzymology/*pathology, Middle Aged, Prognosis, Proportional Hazards Models, Statistics; Nonparametric, Survival Analysis, Tryptases/analysis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-12998 (URN)10.1111/j.1365-2141.2007.06612.x (DOI)000247111300006 ()17555448 (PubMedID)
Available from: 2008-06-04 Created: 2008-06-04 Last updated: 2017-12-11Bibliographically approved
2. Low expression of microRNA-129-5p predicts poor clinical outcome in diffuse large B cell lymphoma (DLBCL)
Open this publication in new window or tab >>Low expression of microRNA-129-5p predicts poor clinical outcome in diffuse large B cell lymphoma (DLBCL)
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2013 (English)In: International Journal of Hematology, ISSN 0925-5710, E-ISSN 1865-3774, Vol. 97, no 4, 465-471 p.Article in journal (Refereed) Published
Abstract [en]

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.

Keyword
DLBCL, microRNA-129-5p, Prognosis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-200079 (URN)10.1007/s12185-013-1303-2 (DOI)000317475500005 ()
Available from: 2013-05-23 Created: 2013-05-20 Last updated: 2017-12-06Bibliographically approved
3. The MDM2 polymorphism SNP309 is associated with clinical characteristics and outcome in diffuse large B-cell lymphoma
Open this publication in new window or tab >>The MDM2 polymorphism SNP309 is associated with clinical characteristics and outcome in diffuse large B-cell lymphoma
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2014 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 93, no 6, 500-508 p.Article in journal (Refereed) Published
Abstract [en]

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.

National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-219350 (URN)10.1111/ejh.12388 (DOI)000345302700006 ()24889555 (PubMedID)
Available from: 2014-02-27 Created: 2014-02-27 Last updated: 2017-12-05Bibliographically approved
4. Impact of age in an unselected population of Diffuse large B-cell lymphomas
Open this publication in new window or tab >>Impact of age in an unselected population of Diffuse large B-cell lymphomas
2014 (English)Article in journal (Refereed) Submitted
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-219351 (URN)
Available from: 2014-02-27 Created: 2014-02-27 Last updated: 2014-06-05Bibliographically approved

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