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  • 1. Aleskog, Anna
    et al.
    Tobin, Gerard
    Laurell, Anna
    Thunberg, Ulf
    Lindhagen, Elin
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Nilsson, Kenneth
    Nygren, Peter
    Sundström, Christer
    Hägglund, Martin
    Larsson, Rolf
    Rosenquist, Richard
    VH gene mutation status and cellular drug resistance in chronic lymphocytic leukaemia.2004In: Eur J Haematol, ISSN 0902-4441, Vol. 73, no 6, 407-11 p.Article in journal (Refereed)
  • 2.
    Andersson, Ulrika
    et al.
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Osterman, Pia
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Sjöström, Sara
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Johansen, Christoffer
    Henriksson, Roger
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Brännström, Thomas
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Broholm, Helle
    Christensen, Helle Collatz
    Ahlbom, Anders
    Auvinen, Anssi
    Feychting, Maria
    Lönn, Stefan
    Kiuru, Anne
    Swerdlow, Anthony
    Schoemaker, Minouk
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Malmer, Beatrice
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    MNS16A minisatellite genotypes in relation to risk of glioma and meningioma and to glioblastoma outcome.2009In: International journal of cancer. Journal international du cancer, ISSN 1097-0215, Vol. 125, no 4, 968-972 p.Article in journal (Refereed)
    Abstract [en]

    The human telomerase reverse transcriptase (hTERT) gene is upregulated in a majority of malignant tumours. A variable tandem repeat, MNS16A, has been reported to be of functional significance for hTERT expression. Published data on the clinical relevance of MNS16A variants in brain tumours have been contradictory. The present population-based study in the Nordic countries and the United Kingdom evaluated brain-tumour risk and survival in relation to MNS16A minisatellite variants in 648 glioma cases, 473 meningioma cases and 1,359 age, sex and geographically matched controls. By PCR-based genotyping all study subjects with fragments of 240 or 271 bp were judged as having short (S) alleles and subjects with 299 or 331 bp fragments as having long (L) alleles. Relative risk of glioma or meningioma was estimated with logistic regression adjusting for age, sex and country. Overall survival was analysed using Kaplan-Meier estimates and equality of survival distributions using the log-rank test and Cox proportional hazard ratios. The MNS16A genotype was not associated with risk of occurrence of glioma, glioblastoma (GBM) or meningioma. For GBM there were median survivals of 15.3, 11.0 and 10.7 months for the LL, LS and SS genotypes, respectively; the hazard ratio for having the LS genotype compared with the LL was significantly increased HR 2.44 (1.56-3.82) and having the SS genotype versus the LL was nonsignificantly increased HR 1.46 (0.81-2.61). When comparing the LL versus having one of the potentially functional variants LS and SS, the HR was 2.10 (1.41-3.1). However, functionality was not supported as there was no trend towards increasing HR with number of S alleles. Collected data from our and previous studies regarding both risk and survival for the MNS16A genotypes are contradictory and warrant further investigations.

  • 3. Berglund, Mattias
    et al.
    Amini, Rose-Marie
    Book, Majlis
    Rosenquist, Richard
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Thunberg, Ulf
    Subtype preference of the BCL6397G/C polymorphism in germinal-center and non-germinal-center subtypes of diffuse large B-cell lymphoma.2006In: Blood, ISSN 0006-4971, Vol. 108, no 10, 3623-4 p.Article in journal (Other academic)
  • 4. Berglund, Mattias
    et al.
    Enblad, Gunilla
    Thunberg, Ulf
    Amini, Rose-Marie
    Sundström, Christer
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Rosenquist, Richard
    Larsson, Catharina
    Lagercrantz, Svetlana
    Genomic imbalances during transformation from follicular lymphoma to diffuse large B-cell lymphoma.2007In: Modern Patholology, ISSN 0893-3952, Vol. 20, no 1, 63-75 p.Article in journal (Refereed)
  • 5. Berglund, Mattias
    et al.
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Thunberg, Ulf
    Thymidylate syntase polymorphism relevant for survival in patients with diffuse large B-cell lymphoma?2009In: Leukemia & lymphoma, ISSN 1029-2403, Vol. 50, no 10, 1723-1725 p.Article in journal (Refereed)
  • 6. Berglund, Mattias
    et al.
    Thunberg, Ulf
    Amini, Rose-Marie
    Book, Majlis
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Erlanson, Martin
    Linderoth, Johan
    Dictor, Michael
    Jerkeman, Mats
    Cavallin-Ståhl, Eva
    Sundström, Christer
    Rehn-Eriksson, Suzanne
    Backlin, Carin
    Hagberg, Hans
    Rosenquist, Richard
    Enblad, Gunilla
    Evaluation of immunophenotype in diffuse large B-cell lymphoma and its impact on prognosis.2005In: Mod Pathol, ISSN 0893-3952, Vol. 18, no 8, 1113-20 p.Article in journal (Refereed)
  • 7. Berglund, Mattias
    et al.
    Thunberg, Ulf
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Rosenquist, Richard
    Enblad, Gunilla
    The interleukin-10 gene promoter polymorphism (-1082) does not correlate with clinical outcome in diffuse large B-cell lymphoma.2005In: Blood, ISSN 0006-4971, Vol. 105, no 12, 4894-5; author reply 4895 p.Article in journal (Other academic)
  • 8.
    Borssen, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Cullman, Inger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Sundstrom, Christer
    Porwit, Anna
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia-associations with immunophenotype and cytogenetic subgroup2011In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 39, no 12, 1144-1151 p.Article in journal (Refereed)
    Abstract [en]

    Telomere maintenance, important for long-term cell survival and malignant transformation, is directed by a multitude of factors, including epigenetic mechanisms, and has been implicated in outcomes for patients with leukemia. In the present study, the objective was to investigate the biological and clinical significance of telomere length and promoter methylation of the human telomerase reverse transcriptase gene in childhood acute lymphoblastic leukemia. A cohort of 169 childhood acute lymphoblastic leukemias was investigated for telomere length, human telomerase reverse transcriptase gene promoter methylation status, genomic aberrations, immunophenotype, and clinical outcomes. Methylation of the core promoter of the human telomerase reverse transcriptase (hTERT) gene was demonstrated in 24% of diagnostic samples, with a significant difference between B-cell precursor (n = 130) and T-cell acute lymphoblastic leukemia (ALL) (n = 17) cases (18% and 72%, respectively; p < 0.001). No remission sample demonstrated hTERT promoter methylation (n = 40). Within the B-cell precursor group, t(12;21)(p13;q22) [ETV6/RUNX1] cases (n = 19) showed a much higher frequency of hTERT methylation than high-hyperdiploid (51 61 chromosomes) ALL (n = 44) (63% and 7%, respectively; p < 0.001). hTERT messenger RNA levels were negatively associated with methylation status and, in the t(12;21) group, methylated cases had shorter telomeres (p = 0.017). In low-risk B-cell precursor patients (n = 101), long telomeres indicated a worse prognosis. The collected data from the present study indicate that the telomere biology in childhood ALL has clinical implications and reflects molecular differences between diverse ALL subgroups. (C) 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

  • 9.
    Borssen, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Lars
    Karrman, Kristina
    Abrahamsson, Jonas
    Behrendtz, Mikael
    Heldrup, Jesper
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, e65373- p.Article in journal (Refereed)
    Abstract [en]

    Background: Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has improved, but there is a considerable fraction of patients experiencing a poor outcome. There is a need for better prognostic markers and aberrant DNA methylation is a candidate in other malignancies, but its potential prognostic significance in T-ALL is hitherto undecided.

    Design and Methods: Genome wide promoter DNA methylation analysis was performed in pediatric T-ALL samples (n = 43) using arrays covering >27000 CpG sites. Clinical outcome was evaluated in relation to methylation status and compared with a contemporary T-ALL group not tested for methylation (n = 32).

    Results: Based on CpG island methylator phenotype (CIMP), T-ALL samples were subgrouped as CIMP+ (high methylation) and CIMP- (low methylation). CIMP- T-ALL patients had significantly worse overall and event free survival (p = 0.02 and p = 0.001, respectively) compared to CIMP+ cases. CIMP status was an independent factor for survival in multivariate analysis including age, gender and white blood cell count. Analysis of differently methylated genes in the CIMP subgroups showed an overrepresentation of transcription factors, ligands and polycomb target genes.

    Conclusions: We identified global promoter methylation profiling as being of relevance for subgrouping and prognostication of pediatric T-ALL.

  • 10. Buckley, Patrick G
    et al.
    Walsh, Sarah H
    Laurell, Anna
    Sundström, Christer
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Langford, Cordelia F
    Dumanski, Jan P
    Rosenquist, Richard
    Genome-wide microarray-based comparative genomic hybridization analysis of lymphoplasmacytic lymphomas reveals heterogeneous aberrations.2009In: Leukemia & lymphoma, ISSN 1029-2403, Vol. 50, no 9, 1528-1534 p.Article in journal (Refereed)
    Abstract [en]

    Lymphoplasmacytic lymphoma (LPL) is not a sharply delineated lymphoma entity, either morphologically, phenotypically, or clinically. The diagnosis is often made by excluding other small cell lymphomas with plasmacytic differentiation, thus a genetic diagnostic marker would be of great benefit. Conventional cytogenetic techniques have previously demonstrated a deletion of 6q in a proportion of cases, varying from 7 to 55%. In this report, we apply array-based comparative genomic hybridization on 11 LPL samples. Genomic aberrations were detected in 9 of 11 cases, and included gains and losses. In general, the number of genetic aberrations was relatively low (two to three abnormalities per case). Recurrent aberrations detected were deletion of 6q (two cases), deletion of chromosome 17 (two cases), gain of 3q (two cases), and gain of chromosome 7 (two cases). This report not only confirms the reported loss of 6q in a proportion of cases but also highlights the genetic heterogeneity of LPL, in accordance with the known immunophenotypical, morphological, and clinical diversity of the disease.

  • 11. Chang, Ellen T
    et al.
    Smedby, Karin Ekström
    Hjalgrim, Henrik
    Porwit-MacDonald, Anna
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Glimelius, Bengt
    Adami, Hans-Olov
    Family history of hematopoietic malignancy and risk of lymphoma.2005In: J Natl Cancer Inst, ISSN 1460-2105, Vol. 97, no 19, 1466-74 p.Article in journal (Refereed)
  • 12. de Almeida, Fernando J. Mota
    et al.
    Kivijarvi, Kristina
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    A case of disseminated histoplasmosis diagnosed after oral presentation in an old HIV-negative patient in Sweden2015In: Gerodontology, ISSN 0734-0664, E-ISSN 1741-2358, Vol. 32, no 3, 234-236 p.Article in journal (Refereed)
    Abstract [en]

    Histoplasmosis is an endemic disease in various regions such as North America and South-East Asia but remains rare in Europe. Disseminated histoplasmosis is unusual in HIV-negative patients. Here, we describe a case of disseminated histoplasmosis in an HIV-negative patient diagnosed after oral presentation.

  • 13.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Borssen, Magnus
    Umeå University, Faculty of Medicine. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersson, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Chranowska, Krystyna H.
    Department of Medical Genetics, Childrens Memorial Health institute, 04-730 Warsaw, Poland.
    Siwicki, Jan Konrad
    Department of Immunology, maria Sklodowska-Curie Memorial Cancer Centre and institute of Oncology, 02-781, Warsaw, Poland.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Senescence bypass and immortalization of T cell cultures are linked to stepwise DNA methylation changesManuscript (preprint) (Other academic)
  • 14.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Domellöf, Magdalena
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Linder, Jan
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Lundin, Mathias
    Umeå University, Faculty of Social Sciences, Umeå School of Business and Economics (USBE), Statistics.
    Haraldsson, Susann
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Elgh, Eva
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forsgren, Lars
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Neuroscience.
    Long Leukocyte Telomere Length at Diagnosis Is a Risk Factor for Dementia Progression in Idiopathic Parkinsonism2014In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, e113387Article in journal (Refereed)
    Abstract [en]

    Telomere length (TL) is regarded as a marker of cellular aging due to the gradual shortening by each cell division, but is influenced by a number of factors including oxidative stress and inflammation. Parkinson's disease and atypical forms of parkinsonism occur mainly in the elderly, with oxidative stress and inflammation in afflicted cells. In this study the relationship between blood TL and prognosis of 168 patients with idiopathic parkinsonism (136 Parkinson's disease [PD], 17 Progressive Supranuclear Palsy [PSP], and 15 Multiple System Atrophy [MSA]) and 30 controls was investigated. TL and motor and cognitive performance were assessed at baseline (diagnosis) and repeatedly up to three to five years follow up. No difference in TL between controls and patients was shown at baseline, nor any significant difference in TL stability or attrition during follow up. Interestingly, a significant relationship between TL at diagnosis and cognitive phenotype at follow up in PD and PSP patients was found, with longer mean TL at diagnosis in patients that developed dementia within three years.

  • 15.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Siwicki, Jan Konrad
    Revie, John
    Borssen, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Evelönn, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Chrzanowska, Krystyna H.
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Keith, W. Nicol
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias2014In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, no 7, 606-615 p.Article in journal (Refereed)
    Abstract [en]

    We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.

  • 16.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Siwicki, Jan Konrad
    Department of Immunology, Maria Sklodowska-Curie memorial Cancer Centre and Institute of Oncology, 02-781 Warsaw, Poland.
    Osterman, Pia
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lafferty-Whyte, Kyle
    Centre of Oncology and Applied Pharmacology, Cancer research UK Beatson Laboratories, University of Glasgow, Scotland.
    Keith, W. Nicol
    Centre of Oncology and Applied Pharmacology, Cancer research UK Beatson Laboratories, University of Glasgow, Scotland.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomerase upregulation is a postcrisis event during senescence bypass and immortalization of two Nijmegen breakage syndrome T cell cultures2010In: Aging Cell, ISSN 1474-9718, E-ISSN 1474-9726, Vol. 9, 220-235 p.Article in journal (Refereed)
    Abstract [en]

    Summary Our knowledge on immortalization and telomere biology is mainly based on genetically manipulated cells analyzed before and many population doublings post growth crisis. The general view is that growth crisis is telomere length (TL) dependent and that escape from crisis is coupled to increased expression of the telomerase reverse transcriptase (hTERT) gene, telomerase activity upregulation and TL stabilization. Here we have analyzed the process of spontaneous immortalization of human T cells, regarding pathways involved in senescence and telomerase regulation. Two Nijmegen breakage syndrome (NBS) T cell cultures (S3R and S4) showed gradual telomere attrition until a period of growth crisis followed by the outgrowth of immortalized cells. Whole genome expression analysis indicated differences between pre-, early post- and late postcrisis cells. Early postcrisis cells demonstrated a logarithmic growth curve, very short telomeres and, notably, no increase in hTERT or telomerase activity despite downregulation of several negative hTERT regulators (e.g. FOS, JUN D, SMAD3, RUNX2, TNF-alpha and TGFbeta-R2). Thereafter, cMYC mRNA increased in parallel with increased hTERT expression, telomerase activity and elongation of short telomeres, indicating a step-wise activation of hTERT transcription involving reduction of negative regulators followed by activation of positive regulator(s). Gene expression analysis indicated that cells escaped growth crisis by deregulated DNA damage response and senescence controlling genes, including downregulation of ATM, CDKN1B (p27), CDKN2D (p19) and ASF1A and upregulation of CDK4, TWIST1, TP73L (p63) and SYK. Telomerase upregulation was thus found to be uncoupled to escape of growth crisis but rather a later event in the immortalization process of NBS T cell cultures.

  • 17.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Tumkur Sitaram, Raviprakash
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The NBS1 gene is overexpressed and regulated by DJ-1 in clear cell renal cell carcinomaManuscript (preprint) (Other academic)
  • 18.
    Ebrahimi, Majid
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Umeå University, Faculty of Medicine, Department of Odontology.
    Wahlin, Ylva-Britt
    Umeå University, Faculty of Medicine, Department of Odontology, Oral and Maxillofacial Radiology.
    Coates, Philip J
    Wiik, Allan
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nylander, Karin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Detection of antibodies against p63 and p73 isoforms in sera from patients diagnosed with oral lichen planus.2007In: Journal of Oral Pathology & Medicine, ISSN 0904-2512, E-ISSN 1600-0714, Vol. 36, no 2, 93-98 p.Article in journal (Refereed)
    Abstract [en]

    Background: Oral lichen planus (OLP) is a chronic inflammatory disease of oral mucosa. Despite numerous publications and intense research, the etiology of OLP is still unknown, however, autoimmunity as a possible causative factor has been discussed. Methods: In the present study sera from 20 patients clinically and histologically diagnosed with OLP were analyzed for antibodies directed toward p53, p63, and p73 using Western blot. Results: Sera from two patients reacted with all six p63 isoforms, and one also with p73. The strongest reaction was noted against the TAp63beta protein, which is the most potent transactivator of all p63 proteins and is implicated in the differentiation of stratified epithelia. Conclusions: This is the first demonstration of antibodies directed against all p63 and some p73 isoforms in sera from patients diagnosed with OLP.

  • 19.
    Eriksson, Björn
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Johansson, Ann-Sofie
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Levan, Göran
    Holmberg, Dan
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Establishment and characterization of a mouse strain (TLL) that spontaneously develops T-cell lymphomas/leukemia1999In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 27, no 4, 682-688 p.Article in journal (Refereed)
    Abstract [en]

    In this study, a mouse strain (TLL) that spontaneously develops T-cell lymphomas/leukemia with an early onset and high incidence was established and characterized. All tumors analyzed were found to express the alpha,beta T-cell receptor, and the majority of them had a mature, CD3+CD4+CD8- immunophenotype. In a few cases, tumors with a more immature CD3+CD4+CD8+ phenotype were isolated. Expanded phenotyping using a broad panel of lymphocyte differentiation markers confirmed the mature T-cell phenotype of the tumors. Histologic and cell cycle analysis of the tumors revealed an aggressive lymphoblastic malignancy with a very high proliferation rate and widespread engagement of bone marrow and lymphoid as well as nonlymphoid organs. Thus, the TLL mouse strain represents a unique model for the analysis of the oncogenesis and progression of mature T-cell tumors and for the development of therapeutic measures to combat such tumors.

  • 20.
    Grabowski, Pawel
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Karlsson, Karin
    Tobin, Gerard
    Aleskog, Anna
    Thunberg, Ulf
    Laurell, Anna
    Sundström, Christer
    Rosenquist, Richard
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere length as a prognostic parameter in chronic lymphocytic leukemia with special reference to VH gene mutation status2005In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 105, no 12, 4807-4812 p.Article in journal (Refereed)
    Abstract [en]

    B-cell chronic lymphocytic leukemia (CLL) consists of 2 prognostic entities where cases with mutated immunoglobulin VH genes have better outcome than unmutated cases. VH-mutated CLLs display longer telomeres compared with unmutated cases and telomere length has been indicated to predict outcome, although the prognostic value of telomere length has not been fully established in CLL. We analyzed telomere length, VH gene mutation status, and clinical parameters in a large series of CLL. Telomere length was assessed by quantitative polymerase chain reaction (PCR), giving a very good correlation to telomere length estimated by Southern blotting (P < .001). The prognostic information given by mutation status (n = 282) and telomere length (n = 246) was significant (P < .001, respectively). Telomere length was a prognostic factor for stage A (P = .021) and stage B/C (P = .018) patients, whereas mutation status predicted outcome only in stage A patients (P < .001). Furthermore, mutated CLLs were subdivided by telomere length into 2 groups with different prognoses (P = .003), a subdivision not seen for unmutated cases (P = .232). Interestingly, the VH-mutated group with short telomeres had an overall survival close to that of the unmutated cases. Thus, by combining VH mutation status and telomere length, an improved subclassification of CLL was achieved identifying previously unrecognized patient groups with different outcomes.

  • 21. Hansson, Maire
    et al.
    Zendehrokh, Nooreldin
    Ohyashiki, Junko
    Ohyashiki, Kazuma
    Westman, Ulla-Britt
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Dejmek, Annika
    Telomerase activity in effusions: a comparison between telomere repeat amplification protocol in situ and conventional telomere repeat amplification protocol assay.2008In: Arch Pathol Lab Med, ISSN 1543-2165, Vol. 132, no 12, 1896-1902 p.Article in journal (Other academic)
  • 22.
    Hedberg, Ylva
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Landberg, Göran
    Retinoblastoma protein in human renal cell carcinoma in relation to alterations in G1/S regulatory proteins.2004In: International journal of cancer, ISSN 0020-7136, Vol. 109, no 2, 189-93 p.Article in journal (Refereed)
  • 23. Hedström, Gustaf
    et al.
    Berglund, Mattias
    Molin, Daniel
    Fischer, Marie
    Nilsson, Gunnar
    Thunberg, Ulf
    Book, Majlis
    Sundström, Christer
    Rosenquist, Richard
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Amini, Rose-Marie
    Enblad, Gunilla
    Mast cell infiltration is a favourable prognostic factor in diffuse large B-cell lymphoma.2007In: Br J Haematol, ISSN 0007-1048, Vol. 138, no 1, 68-71 p.Article in journal (Other academic)
  • 24. Hosen, Ismail
    et al.
    Rachakonda, P. Sivaramakrishna
    Heidenreich, Barbara
    Sitaram, Raviprakash T.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Hemminki, Kari
    Kumar, Rajiv
    TERT promoter mutations in clear cell renal cell carcinoma2015In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 136, no 10, 2448-2452 p.Article in journal (Refereed)
    Abstract [en]

    We screened promoter region of the telomerase reverse transcriptase (TERT) for activating somatic mutations in 188 tumors from patients with clear cell renal cell carcinoma (ccRCC). Twelve tumors (6.4%) carried a mutation within the core promoter region of the gene. The mutations were less frequent in high grade tumors compared to low grade tumors [odds ratio (OR)=0.15, 95% confidence interval (CI)=0.03-0.72, p=0.02]. Multivariate analysis for cause specific survival showed statistically significant poor outcome in patients with TERT promoter mutations [hazard ratio (HR)=2.90, 95% CI=1.13-7.39, p=0.03]. A common polymorphism (rs2853669) within the locus seemed to act as a modifier of the effect of the mutations on patient survival as the noncarriers of the variant allele with the TERT promoter mutations showed worst survival (HR=3.34, 95% CI=1.24-8.98, p=0.02). We also measured relative telomere length (RTL) in tumors and difference between tumors with and without the TERT promoter mutations was not statistically significant. Similarly, no difference in patient survival based on RTL in tumors was observed. Our study showed a relatively low frequency of TERT promoter mutations in ccRCC. Nevertheless, patients with the mutations, particularly in the absence of the rs2853669 variant showed the worst disease-specific survival. Thus, it is possible that the TERT promoter mutations define a small subset of tumors with an aggressive behavior. What's new? The human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase, a ribonucleoprotein complex that maintains genomic integrity. Activating somatic mutations in the promoter region of the TERT gene have been reported in many cancers. Here, the authors describe new TERT promoter mutations in clear cell renal cell carcinoma. Although present only in a proportion of the tumors, the TERT promoter mutations were independently associated with poor patient survival. The effect was enhanced by a common polymorphism within the core TERT promoter. The TERT promoter mutations may thus define a small subset of tumors with an aggressive behavior.

  • 25.
    Hultdin, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Grönlund, Elisabeth
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Eriksson-Lindström, E
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Just, T
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere analysis by fluorescence in situ hybridization and flow cytometry1998In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 26, no 16, 3651-3656 p.Article in journal (Refereed)
    Abstract [en]

    Determination of telomere length is traditionally performed by Southern blotting and densitometry, giving a mean telomere restriction fragment (TRF) value for the total cell population studied. Fluorescence in situ hybridization (FISH) of telomere repeats has been used to calculate telomere length, a method called quantitative (Q)-FISH, We here present a quantitative flow cytometric approach, Q-FISHFCM, for evaluation of telomere length distribution in individual cells based on in situ hybridization using a fluorescein-labeled peptide nucleic acid (PNA) (CCCTAA)(3) probe and DMA staining with propidium iodide, A simple and rapid protocol with results within 30 h was developed giving high reproducibility, One important feature of the protocol was the use of an internal cell line control, giving an automatic compensation for potential differences in the hybridization steps. This protocol was tested successfully on cell lines and clinical samples from bone marrow, blood, lymph nodes and tonsils. A significant correlation was found between Southern blotting and Q-FISHFCM telomere length values (P = 0.002), The mean sub-telomeric DNA length of the tested cell lines and clinical samples was estimated to be 3.2 kbp, With the Q-FISHFCM method the fluorescence signal could be determined in different cell cycle phases, indicating that in human cells the vast majority of telomeric DNA is replicated early in S phase.

  • 26.
    Hultdin, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Grönlund, Elisabeth
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Just, T
    Department of Immunocytochemistry, DAKO A/S, Glostrup, Denmark.
    Taneja, K
    Boston Probes Inc., Bedford, Massachusetts, USA.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Replication timing of human telomeric DNA and other repetitive sequences analyzed by fluorescence in situ hybridization and flow cytometry2001In: Experimental Cell Research, ISSN 0014-4827, Vol. 271, 223-229 p.Article in journal (Refereed)
    Abstract [en]

    The replication timing of telomeres seems to differ between species. Yeast telomeres are late replicating, whereas limited data from very few human cell lines have indicated telomere replication throughout S phase. In the present study a series of permanent cell lines and patient samples was investigated using a flow cytometric approach for telomere length determination based on in situ hybridization using peptide nucleic acid probes and DNA staining. This method permits selective analysis of cells in specific phases of the cell cycle without perturbation of the cell cycle machinery. The timing of replication of telomeric C(3)TA(2) and T(2)AG(3) repeats was found to differ between individual samples and could precede or be concomitant with the replication of bulk DNA. Replication of the T(2)AG(3) strand seemed to occur somewhat later than that of the C(3)TA(2) strand in some samples. (GTG)(n) and other repetitive sequences generally showed a replication pattern similar to that of the bulk of DNA with slightly individual differences, whereas centromeric DNA repeats consistently replicated within a short time frame in late S phase. The apparent variability in replication timing seen for telomeric DNA might suggest individual differences in firing of replication origins.

  • 27.
    Hultdin, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rosenquist, R
    Thunberg, U
    Tobin, G
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Johnson, A
    Sundström, C
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Association between telomere length and V-H gene mutation status in chronic lymphocytic leukaemia: clinical and biological implications2003In: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 88, no 4, 593-598 p.Article in journal (Refereed)
    Abstract [en]

    The immunoglobulin V-H gene mutation status can divide B-cell chronic lymphocytic leukaemia (CLL) into two entities with a different clinical course. Cases with unmutated V-H genes, considered to evolve from pregerminal centre (GC) cells, have a worse outcome compared to cases showing mutated VH genes, that is, post-GC derived. Also, telomere length has been reported to be of prognostic significance in CLL. Interestingly, telomerase becomes activated during the GC reaction and an elongation of the telomeres occurs in GC B cells. We performed telomere length and VH gene analysis in a series of 61 CLL cases, in order to investigate if the unique telomere lengthening shown in GC B cells could reflect the telomere status in the two subsets of mutated and unmutated CLL. A novel association was found between VH gene mutation status and telomere length, since significantly shorter telomeres were demonstrated in the unmutated group compared to the mutated group (mean length 4.3 vs 63 kbp). Shorter telomeres also constituted a subgroup with a worse prognosis than cases with longer telomeres (median survival 59 vs 159 months), Furthermore, the I-g gene sequence data revealed that samples with high mutations frequency (> 6%) had long telomeres (similar to 8 kbp). Thus, both the telomere and VH gene mutation status in CLL appear linked, which may reflect the proliferative history of the clonal cells with regard to the GC reaction. (C) 2003 Cancer Research UK.

  • 28. Kaderi, M A
    et al.
    Norberg, M
    Murray, F
    Merup, M
    Sundström, C
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Aleskog, A
    Karlsson, K
    Axelsson, T
    Tobin, G
    Rosenquist, R
    The BCL-2 promoter (-938C>A) polymorphism does not predict clinical outcome in chronic lymphocytic leukemia.2008In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 22, no 2, 339-343 p.Article in journal (Other academic)
  • 29. Kaderi, Mohd Arifin
    et al.
    Murray, Fiona
    Jansson, Mattias
    Merup, Mats
    Karlsson, Karin
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Aleskog, Anna
    Tobin, Gerard
    The GNAS1 T393C polymorphism and lack of clinical prognostic value in chronic lymphocytic leukemia.2007In: Leuk Res, ISSN 0145-2126, Vol. 36, no 2, 984-987 p.Article in journal (Refereed)
  • 30.
    Köhn, Linda
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Ljungberg, Börje
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Specific Genomic Aberrations Predict Survival, But Low Mutation Rate in Cancer Hot Spots, in Clear Cell Renal Cell Carcinoma2015In: Applied immunohistochemistry & molecular morphology (Print), ISSN 1541-2016, E-ISSN 1533-4058, Vol. 23, no 5, 334-342 p.Article in journal (Refereed)
    Abstract [en]

    Detailed genetic profiling of clear cell renal cell carcinoma (ccRCC) has revealed genomic regions commonly affected by structural changes and a general genetic heterogeneity. VHL and PBRM1, both located at chromosome 3p, are 2 major genes mutated at high frequency but apart from these aberrations, the mutational landscape in ccRCC is largely undefined. Potential prognostic information given by the genomic changes appears to depend on the particular cohort studied. We analyzed a Swedish ccRCC cohort of 74 patients and found common changes (loss or gain occurring in >20% of the tumors) in 12 chromosomal regions (1p, 3p, 3q, 5q, 6q, 7p, 7q 8p, 9p, 9q, 10q, and 14q). A poor outcome was associated with gain of 7q and losses on 9p, 9q, and 14q. These aberrations were more frequent in metastasized tumors, suggesting alterations of genes important for tumor progression. Sequencing of 48 genes implicated in cancer revealed that only VHL, TP53, and PTEN were mutated at a noticeable frequency (51%, 9%, and 9%, respectively). Shorter relative telomere length (RTL) has been associated with loss of specific chromosomal regions in ccRCC tumors, but we could not verify this finding. However, a significantly lower tumor/nontumor (T/N) RTL ratio was detected for tumors with losses in 4q or 9p. In conclusion, poor outcome in ccRCC was associated with gain of 7q and loss on 9p, 9q, and 14q, whereas the mutation rate overall was low in a screen of cancer-associated genes.

  • 31.
    Li, Aihong
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Rosenquist, Richard
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Minimal residual disease quantification in childhood acute lymphoblastic leukemia by real-time polymerase chain reaction using the SYBR green dye.2002In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 30, no 10, 1170-1177 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Clone specific immunoglobulin (Ig) and T-cell receptor (TCR) gene sequences can be used as molecular targets for detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). Real-time quantitative PCR (RQ-PCR) with no need for post-PCR processing is an attractive approach for detection and quantification of specific DNA or RNA sequences. In the present study we evaluated a real-time PCR-based technology for MRD quantification in children with precursor-B ALL. MATERIALS AND METHODS: DNA samples from 36 children with newly diagnosed precursor-B ALL were available for molecular analysis. All patients were uniformly treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) protocols from 1992. A real-time PCR assay was applied for MRD quantification using LightCycler technology and the SYBR green fluorescent dye for detection of clone-specific Ig and TCR gene rearrangements as target sequences. The specificity of the PCR products was verified by melting curve analysis. RESULTS: Thirty-four of the 36 children with precursor-B ALL (94%) displayed at least one clonal Ig heavy chain (IgH) or TCR gene sequence useful as a molecular target. These clone-specific targets were successfully applied for real-time PCR quantification in all but one patient. Melting curve analysis was important for identifying all specific PCR products. In 32 pediatric precursor-B-ALL patients an MRD level >/=10(-3) at day 29 during induction treatment was significantly correlated with later bone marrow relapse (p = 0.0025). CONCLUSIONS: Real-time PCR using clone-specific primers and the SYBR green dye for detection is a feasible technique for identifying patients at risk for relapse. This approach provides an easily applicable tool for detection of IgH/TCR gene rearrangements in the routine setting. Melting curve analysis allowed clear distinction between specific rearrangements and unspecific background signals.

  • 32.
    Li, Aihong
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Rosenquist, R
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Holmberg, D
    Lindh, Jack
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Löfvenberg, E
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Clonal rearrangements in childhood and adult precursor B acute lymphoblastic leukemia: a comparative polymerase chain reaction study using multiple sets of primers.1999In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 63, no 4, 211-8 p.Article in journal (Refereed)
    Abstract [en]

    Ig heavy chain (IgH) and T-cell receptor (TCR) gene rearrangements were investigated by polymerase chain reaction (PCR) amplification of diagnostic tumour samples from 91 patients (57 children and 34 adults, with cut-off at age 16) with precursor B acute lymphoblastic leukemia (ALL). Using primers directed to the framework regions (FR) 1, 2 and 3 of the IgH gene, clonal IgH rearrangements were observed in 82, 58 and 58%, respectively, whereas clonality was presented in 45 and 27% using primers hybridising to the TCR delta and gamma genes. A combination of all five primer sets used resulted in 96% positive cases (children 100%, adults 88%). The frequency of clonal IgH rearrangements correlated to patient age with a significantly lower fraction of positive cases in the adult group. The concomitant usage of more than one V(H) family gene was similar for childhood and adult ALL, and an over-representation of V(H)6 rearrangements was found in childhood ALL. Twenty-five out of 91 cases (27%) displayed an oligoclonal pattern for either IgH or TCR gene rearrangements (children 37%, adults 12%). A comparative analysis of samples from different compartments was performed in 23 patients, and differences between two or three compartments were observed in seven cases. Unexpectedly large, clonally appearing PCR products of 540-715 bp were found in three leukemias and sequence analysis verified their clonal nature. In summary, using multiple sets of primers clonal rearrangements of IgH and TCR genes can be detected in a very high frequency, including previously neglected large size PCR products. A common heterogeneity was demonstrated in different compartments reflecting ongoing clonal evolution, which can make detection of minimal residual disease (MRD) in ALL troublesome. Therefore, we suggest that a minimum of three targets should be used to minimise false-negative results.

  • 33.
    Li, Aihong
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Clinical chemistry.
    Rosenquist, R
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Lindh, Jack
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Detailed clonality analysis of relapsing precursor B acute lymphoblastic leukemia: implications for minimal residual disease detection.2001In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 25, no 12, 1033-45 p.Article in journal (Refereed)
    Abstract [en]

    Genetic instability has important implications for detection of minimal residual disease (MRD) when the target is a clonal genetic marker revealed at diagnosis. A successful MRD detection approach requires a stable marker and for lymphoid leukemias clonal rearrangements of immunoglobulin (Ig) and T cell receptor (TCR) genes are commonly used. In the present study, Ig heavy chain (IgH) and TCR (gamma and delta) genes were studied in 18 consecutive, relapsing precursor-B ALL patients. At least one clonal rearrangement was found in all cases at presentation (IgH 94%, TCRgamma 39% and TCRdelta 28%). An altered rearrangement pattern between diagnosis and relapse was demonstrated in 14 patients (78%). At least one stable molecular target was found in 13 out of 18 cases (72%). Clonal differences between diagnostic and relapse samples were explained by: (1) loss of original rearrangements; (2) V(H) to DJ(H) joining; (3) V(H) gene replacement; (4) appearance of new rearrangements. In two cases with apparently new IgH gene rearrangements at relapse extended sequencing of the diagnostic samples revealed minor clonal rearrangements identical to the relapse clones. Interestingly, one patient displayed instability on both the IgH and TCR gene loci, whereas a stable Igkappa rearrangement was found at presentation and relapse. These data show that clonal diversity is common in precursor-B ALL and strongly suggest that MRD detection should include multiple gene targets to minimize false-negative samples. Even so, five of our 18 relapse cases (28%) lacked stable clonal markers and should have been unsuitable for MRD detection.

  • 34. Linderoth, Johan
    et al.
    Edén, Patrik
    Ehinger, Mats
    Valcich, Jeanette
    Jerkeman, Mats
    Bendahl, Pär-Ola
    Berglund, Mattias
    Enblad, Gunilla
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Cavallin-Ståhl, Eva
    Genes associated with the tumour microenvironment are differentially expressed in cured versus primary chemotherapy-refractory diffuse large B-cell lymphoma.2008In: Br J Haematol, ISSN 1365-2141, Vol. 141, no 4, 423-432 p.Article in journal (Refereed)
    Abstract [en]

    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.

  • 35. Linderoth, Johan
    et al.
    Ehinger, Mats
    Jerkeman, Mats
    Bendahl, Pär-Ola
    Åkerman, Måns
    Berglund, Mattias
    Enblad, Gunilla
    Erlanson, Martin
    Umeå University, Faculty of Medicine, Radiation Sciences, Oncology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology.
    Cavallin-Ståhl, Eva
    CD40 expression identifies a prognostically favourable subgroup of diffuse large B-cell lymphoma.2007In: Leuk Lymphoma, ISSN 1042-8194, Vol. 48, no 9, 1774-1779 p.Article in journal (Refereed)
  • 36. Ma, Hongxia
    et al.
    Zhou, Ziyuan
    Wei, Sheng
    Liu, Zhensheng
    Pooley, Karen A
    Dunning, Alison M
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hosgood, H Dean
    Shen, Min
    Wei, Qingyi
    Shortened telomere length is associated with increased risk of cancer: a meta-analysis2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 6, e20466- p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Telomeres play a key role in the maintenance of chromosome integrity and stability, and telomere shortening is involved in initiation and progression of malignancies. A series of epidemiological studies have examined the association between shortened telomeres and risk of cancers, but the findings remain conflicting.

    METHODS: A dataset composed of 11,255 cases and 13,101 controls from 21 publications was included in a meta-analysis to evaluate the association between overall cancer risk or cancer-specific risk and the relative telomere length. Heterogeneity among studies and their publication bias were further assessed by the χ(2)-based Q statistic test and Egger's test, respectively.

    RESULTS: The results showed that shorter telomeres were significantly associated with cancer risk (OR = 1.35, 95% CI = 1.14-1.60), compared with longer telomeres. In the stratified analysis by tumor type, the association remained significant in subgroups of bladder cancer (OR = 1.84, 95% CI = 1.38-2.44), lung cancer (OR = 2.39, 95% CI = 1.18-4.88), smoking-related cancers (OR = 2.25, 95% CI = 1.83-2.78), cancers in the digestive system (OR = 1.69, 95% CI = 1.53-1.87) and the urogenital system (OR = 1.73, 95% CI = 1.12-2.67). Furthermore, the results also indicated that the association between the relative telomere length and overall cancer risk was statistically significant in studies of Caucasian subjects, Asian subjects, retrospective designs, hospital-based controls and smaller sample sizes. Funnel plot and Egger's test suggested that there was no publication bias in the current meta-analysis (P = 0.532).

    CONCLUSIONS: The results of this meta-analysis suggest that the presence of shortened telomeres may be a marker for susceptibility to human cancer, but single larger, well-design prospective studies are warranted to confirm these findings.

  • 37. Machiela, Mitchell J.
    et al.
    Lan, Qing
    Slager, Susan L.
    Vermeulen, Roel C. H.
    Teras, Lauren R.
    Camp, Nicola J.
    Cerhan, James R.
    Spinelli, John J.
    Wang, Sophia S.
    Nieters, Alexandra
    Vijai, Joseph
    Yeager, Meredith
    Wang, Zhaoming
    Ghesquieres, Herve
    Mckay, James
    Conde, Lucia
    de Bakker, Paul I. W.
    Cox, David G.
    Burdett, Laurie
    Monnereau, Alain
    Flowers, Christopher R.
    De Roos, Anneclaire J.
    Brooks-Wilson, Angela R.
    Giles, Graham G.
    Melbye, Mads
    Gu, Jian
    Jackson, Rebecca D.
    Kane, Eleanor
    Purdue, Mark P.
    Vajdic, Claire M.
    Albanes, Demetrius
    Kelly, Rachel S.
    Zucca, Mariagrazia
    Bertrand, Kimberly A.
    Zeleniuch-Jacquotte, Anne
    Lawrence, Charles
    Hutchinson, Amy
    Zhi, Degui
    Habermann, Thomas M.
    Link, Brian K.
    Novak, Anne J.
    Dogan, Ahmet
    Asmann, Yan W.
    Liebow, Mark
    Thompson, Carrie A.
    Ansell, Stephen M.
    Witzig, Thomas E.
    Tilly, Herve
    Haioun, Corinne
    Molina, Thierry J.
    Hjalgrim, Henrik
    Glimelius, Bengt
    Adami, Hans-Olov
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Bracci, Paige M.
    Riby, Jacques
    Smith, Martyn T.
    Holly, Elizabeth A.
    Cozen, Wendy
    Hartge, Patricia
    Morton, Lindsay M.
    Severson, Richard K.
    Tinker, Lesley F.
    North, Kari E.
    Becker, Nikolaus
    Benavente, Yolanda
    Boffetta, Paolo
    Brennan, Paul
    Foretova, Lenka
    Maynadie, Marc
    Staines, Anthony
    Lightfoot, Tracy
    Crouch, Simon
    Smith, Alex
    Roman, Eve
    Diver, W. Ryan
    Offit, Kenneth
    Zelenetz, Andrew
    Klein, Robert J.
    Villano, Danylo J.
    Zheng, Tongzhang
    Zhang, Yawei
    Holford, Theodore R.
    Turner, Jenny
    Southey, Melissa C.
    Clavel, Jacqueline
    Virtamo, Jarmo
    Weinstein, Stephanie
    Riboli, Elio
    Vineis, Paolo
    Kaaks, Rudolph
    Boeing, Heiner
    Tjonneland, Anne
    Angelucci, Emanuele
    Di Lollo, Simonetta
    Rais, Marco
    De Vivo, Immaculata
    Giovannucci, Edward
    Kraft, Peter
    Huang, Jinyan
    Ma, Baoshan
    Ye, Yuanqing
    Chiu, Brian C. H.
    Liang, Liming
    Park, Ju-Hyun
    Chung, Charles C.
    Weisenburger, Dennis D.
    Fraumeni, Joseph F., Jr.
    Salles, Gilles
    Glenn, Martha
    Cannon-Albright, Lisa
    Curtin, Karen
    Wu, Xifeng
    Smedby, Karin E.
    de Sanjose, Silvia
    Skibola, Christine F.
    Berndt, Sonja I.
    Birmann, Brenda M.
    Chanock, Stephen J.
    Rothman, Nathaniel
    Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes2016In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 25, no 8, 1663-1676 p.Article in journal (Refereed)
    Abstract [en]

    Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82, P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51, P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.

  • 38.
    Mansouri, Larry
    et al.
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University; Uppsala, Sweden.
    Grabowski, Pawel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gunnarsson, Rebeqa
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University; Uppsala, Sweden.
    Cahill, Nicola
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University; Uppsala, Sweden.
    Ekström Smedby, Karin
    Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.
    Geisler, Christian
    Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
    Juliusson, Gunnar
    Department of Laboratory Medicine, Stem Cell Center, Hematology and Transplantation, Lund University, Lund, Sweden.
    Rosenquist, Richard
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University; Uppsala, Sweden.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Telomere length is a robust prognostic marker in early chronic lymphocytic leukemiaManuscript (preprint) (Other academic)
  • 39. Mansouri, Larry
    et al.
    Grabowski, Pawel
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Gunnarsson, Rebeqa
    Cahill, Nicola
    Smedby, Karin Ekstrom
    Geisler, Christian
    Juliusson, Gunnar
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Rosenquist, Richard
    Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients2013In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, no 8, 647-651 p.Article in journal (Refereed)
  • 40.
    Mansouri, Mahmoud
    et al.
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Sevov, Marie
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Fahlgren, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Tobin, Gerard
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Jondal, Mikael
    Department of Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Osorio, Lyda
    Department of Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Olivecrona, Gunilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Physiological chemistry.
    Rosenquist, Richard
    Department of Genetics and Pathology, Uppsala University, Uppsala, Sweden.
    Lipoprotein lipase is differentially expressed in prognostic subsets of chronic lymphocytic leukemia but displays invariably low catalytical activity2010In: Leukemia research, ISSN 1873-5835, Vol. 34, no 3, 301-306 p.Article in journal (Refereed)
    Abstract [en]

    Lipoprotein lipase (LPL) expression has been shown to correlate with IGHV mutational status and to predict outcome in chronic lymphocytic leukemia (CLL). We here investigated the prognostic impact of LPL expression in relation to other prognostic markers including IGHV3-21 usage in 140 CLL patients. Additionally, we studied the catalytic activity of LPL in CLL cells. A significant difference in LPL mRNA expression was detected in IGHV unmutated compared to mutated CLL patients (p<0.001). However, the poor-prognostic mutated/stereotyped IGHV3-21 patients did not differ from other mutated CLL cases. Clinical outcome was significantly different in CLL cases with high versus low LPL expression (p<0.001), and LPL expression exceeded mutation status/IGHV3-21 usage as an independent prognostic marker. Finally, LPL protein expression correlated significantly with mRNA expression and was higher in IGHV unmutated versus mutated CLL (p=0.018), although the majority of synthesized protein was catalytically inactive indicating a non-catalytical function in CLL.

  • 41. Martin-Ruiz, Carmen M
    et al.
    Baird, Duncan
    Roger, Laureline
    Boukamp, Petra
    Krunic, Damir
    Cawthon, Richard
    Dokter, Martin M
    Van Der Harst, Pim
    Bekaert, Sofie
    De Meyer, Tim
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Codd, Veryan
    Samani, Nilesh J
    Mcglynn, Liane
    Shiels, Paul G
    Pooley, Karen A
    Dunning, Alison M
    Cooper, Rachel
    Wong, Andrew
    Kingston, Andrew
    Von Zglinicki, Thomas
    Is Southern blotting necessary to measure telomere length reproducibly?: Authors' Response to: Commentary: The reliability of telomere length measurements2015In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, no 5, 1686-1687 p.Article in journal (Other academic)
  • 42. Martin-Ruiz, Carmen M
    et al.
    Baird, Duncan
    Roger, Laureline
    Boukamp, Petra
    Krunic, Damir
    Cawthon, Richard
    Dokter, Martin M
    van der Harst, Pim
    Bekaert, Sofie
    de Meyer, Tim
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Codd, Veryan
    Samani, Nilesh J
    McGlynn, Liane
    Shiels, Paul G
    Pooley, Karen A
    Dunning, Alison M
    Cooper, Rachel
    Wong, Andrew
    Kingston, Andrew
    von Zglinicki, Thomas
    Reproducibility of telomere length assessment: an international collaborative study2015In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, no 5, 1673-1683 p.Article in journal (Refereed)
    Abstract [en]

    Background: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories. Methods: We instigated an international collaborative study of telomere length assessment: 10 different laboratories, employing 3 different techniques [Southern blotting, single telomere length analysis (STELA) and real-time quantitative PCR (qPCR)] performed two rounds of fully blinded measurements on 10 human DNA samples per round to enable unbiased assessment of intra- and inter-batch variation between laboratories and techniques. Results: Absolute results from different laboratories differed widely and could thus not be compared directly, but rankings of relative telomere lengths were highly correlated (correlation coefficients of 0.63-0.99). Intra-technique correlations were similar for Southern blotting and qPCR and were stronger than inter-technique ones. However, inter-laboratory coefficients of variation (CVs) averaged about 10% for Southern blotting and STELA and more than 20% for qPCR. This difference was compensated for by a higher dynamic range for the qPCR method as shown by equal variance after z-scoring. Technical variation per laboratory, measured as median of intra- and inter-batch CVs, ranged from 1.4% to 9.5%, with differences between laboratories only marginally significant (P = 0.06). Gel-based and PCR-based techniques were not different in accuracy. Conclusions: Intra- and inter-laboratory technical variation severely limits the usefulness of data pooling and excludes sharing of reference ranges between laboratories. We propose to establish a common set of physical telomere length standards to improve comparability of telomere length estimates between laboratories.

  • 43. Martin-Ruiz, Carmen M
    et al.
    Baird, Duncan
    Roger, Laureline
    Boukamp, Petra
    Krunic, Damir
    Cawthon, Richard
    Dokter, Martin M
    Van der Harst, Pim
    Bekaert, Sofie
    De Meyer, Tim
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Codd, Veryan
    Samani, Nilesh J
    Mcglynn, Liane
    Shiels, Paul G
    Pooley, Karen A
    Dunning, Alison M
    Cooper, Rachel
    Wong, Andrew
    Kingston, Andrew
    Von Zglinicki, Thomas
    Reproducibility of telomere length assessment: Authors' Response to Damjan Krstajic and Ljubomir Buturovic2015In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, no 5, 1739-1741 p.Article in journal (Refereed)
  • 44.
    Melin, Beatrice S.
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Nordfjall, Katarina
    Andersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    hTERT Cancer Risk Genotypes Are Associated With Telomere Length2012In: Genetic Epidemiology, ISSN 0741-0395, E-ISSN 1098-2272, Vol. 36, no 4, 368-372 p.Article in journal (Refereed)
    Abstract [en]

    Telomere biology is associated with cancer initiation and prognosis. Collected data suggest that blood cell telomere length (TL) can change over time, which may be related to development of common disorders, such as cardiovascular diseases and cancer. Recently, single nucleotide polymorphisms in the region of the human telomerase reverse transcriptase (hTERT) gene were associated with various malignancies, including glioma, lung and urinary bladder cancer, and telomerase RNA gene hTERC genotypes were recently linked to TL. In the present study a hypothetical association between identified genotypes in hTERT and hTERC genes and TL were investigated. We analyzed 21 polymorphisms, covering 90% of the genetic variance, in the hTERT gene, two genetic variants in hTERC, and relative TL(RTL) at average age 50 and 60 in 959 individuals with repeated blood samples. Mean RTL at age 60 was associated with four genetic variants of the hTERT gene (rs2736100, rs2853672, rs2853677, and rs2853676), two of which reported to be associated with cancer risk. Two alleles (rs12696304, rs16847897) near the hTERC gene were confirmed as also being associated with RTL at age 60. Our data suggest that hTERT and hTERC genotypes have an impact on TL of potential relevance and detectable first at higher ages, which gives us further insight to the complex regulation of TL. Genet. Epidemiol. 36:368-372, 2012. (c) 2012 Wiley Periodicals, Inc.

  • 45.
    Nordfjäll, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Melander, Olle
    Nilsson, Peter
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Telomere Length Is Associated With Obesity Parameters but With a Gender Difference.2008In: Obesity (Silver Spring), ISSN 1930-7381, Vol. 16, no 12, 2682-2689 p.Article in journal (Refereed)
  • 46.
    Nordfjäll, Katarina
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Larefalk, Asa
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Lindgren, Petter
    Umeå University, Faculty of Medicine, Medical Biosciences, Medical and Clinical Genetics. Medicinsk och klinisk genetik.
    Holmberg, Dan
    Medicinsk och klinisk genetik.
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Telomere length and heredity: Indications of paternal inheritance.2005In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 102, no 45, 16374-16378 p.Article in journal (Refereed)
  • 47.
    Nordfjäll, Katarina
    et al.
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Osterman, Pia
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    Melander, Olle
    Nilsson, Peter
    Roos, Göran
    Umeå University, Faculty of Medicine, Medical Biosciences, Pathology. Patologi.
    hTERT (-1327)T/C polymorphism is not associated with age-related telomere attrition in peripheral blood.2007In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 358, no 1, 215-218 p.Article in journal (Refereed)
  • 48.
    Nordfjäll, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Lenner, Per
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    The individual blood cell telomere attrition rate is telomere length dependent.2009In: PLoS genetics, ISSN 1553-7404, Vol. 5, no 2, e1000375- p.Article in journal (Refereed)
    Abstract [en]

    Age-associated telomere shortening is a well documented feature of peripheral blood cells in human population studies, but it is not known to what extent these data can be transferred to the individual level. Telomere length (TL) in two blood samples taken at approximately 10 years interval from 959 individuals was investigated using real-time PCR. TL was also measured in 13 families from a multigenerational cohort. As expected, we found an age-related decline in TL over time (r = -0.164, P<0.001, n = 959). However, approximately one-third of the individuals exhibited a stable or increased TL over a decade. The individual telomere attrition rate was inversely correlated with initial TL at a highly significant level (r = -0.752, P<0.001), indicating that the attrition rate was most pronounced in individuals with long telomeres at baseline. In accordance, the age-associated telomere attrition rate was more prominent in families with members displaying longer telomeres at a young age (r = -0.691, P<0.001). Abnormal blood TL has been reported at diagnosis of various malignancies, but in the present study there was no association between individual telomere attrition rate or prediagnostic TL and later tumor development. The collected data strongly suggest a TL maintenance mechanism acting in vivo, providing protection of short telomeres as previously demonstrated in vitro. Our findings might challenge the hypothesis that individual TL can predict possible life span or later tumor development.

  • 49.
    Nordfjäll, Katarina
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Svenson, Ulrika
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norrback, Karl-Fredrik
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Adolfsson, Rolf
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Psychiatry.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Large-scale parent-child comparison confirms a strong paternal influence on telomere length2010In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 18, no 3, 385-389 p.Article in journal (Refereed)
    Abstract [en]

    Telomere length is documented to have a hereditary component, and both paternal and X-linked inheritance have been proposed. We investigated blood cell telomere length in 962 individuals with an age range between 0 and 102 years. Telomere length correlations were analyzed between parent-child pairs in different age groups and between grandparent-grandchild pairs. A highly significant correlation between the father's and the child's telomere length was observed (r=0.454, P<0.001), independent of the sex of the offspring (father-son: r=0.465, P<0.001; father-daughter: r=0.484, P<0.001). For mothers, the correlations were weaker (mother-child: r=0.148, P=0.098; mother-son: r=0.080, P=0.561; mother-daughter: r=0.297, P=0.013). A positive telomere length correlation was also observed for grandparent-grandchild pairs (r=0.272, P=0.013). Our findings indicate that fathers contribute significantly stronger to the telomere length of the offspring compared with mothers (P=0.012), but we cannot exclude a maternal influence on the daughter's telomeres. Interestingly, the father-child correlations diminished with increasing age (P=0.022), suggesting that nonheritable factors have an impact on telomere length dynamics during life.

  • 50.
    Nordfjäll, Kathrine
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Eliasson, Mats
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Stegmayr, Birgitta
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Lundin, S
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Patologi.
    Nilsson, P M
    Increased abdominal obesity, adverse psychosocial factors and shorter telomere length in subjects reporting early ageing; the MONICA Northern Sweden Study.2008In: Scand J Public Health, ISSN 1403-4948, Vol. 36, no 7, 744-752 p.Article in journal (Other academic)
123 1 - 50 of 102
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