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  • 1. Abdulla, Maysaa
    et al.
    Hollander, Peter
    Pandzic, Tatjana
    Mansouri, Larry
    Ednersson, Susanne Bram
    Andersson, Per-Ola
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Fors, Maja
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Erlanson, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Petersen, Helga Munch
    Asmar, Fazila
    Gronbaek, Kirsten
    Enblad, Gunilla
    Cavelier, Lucia
    Rosenquist, Richard
    Amini, Rose-Marie
    Cell-of-origin determined by both gene expression profiling and immunohistochemistry is the strongest predictor of survival in patients with diffuse large B-cell lymphoma2020Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 95, nr 1, s. 57-67Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The tumor cells in diffuse large B-cell lymphomas (DLBCL) are considered to originate from germinal center derived B-cells (GCB) or activated B-cells (ABC). Gene expression profiling (GEP) is preferably used to determine the cell of origin (COO). However, GEP is not widely applied in clinical practice and consequently, several algorithms based on immunohistochemistry (IHC) have been developed. Our aim was to evaluate the concordance of COO assignment between the Lymph2Cx GEP assay and the IHC-based Hans algorithm, to decide which model is the best survival predictor. Both GEP and IHC were performed in 359 homogenously treated Swedish and Danish DLBCL patients, in a retrospective multicenter cohort. The overall concordance between GEP and IHC algorithm was 72%; GEP classified 85% of cases assigned as GCB by IHC, as GCB, while 58% classified as non-GCB by IHC, were categorized as ABC by GEP. There were significant survival differences (overall survival and progression-free survival) if cases were classified by GEP, whereas if cases were categorized by IHC only progression-free survival differed significantly. Importantly, patients assigned as non-GCB/ABC both by IHC and GEP had the worst prognosis, which was also significant in multivariate analyses. Double expression of MYC and BCL2 was more common in ABC cases and was associated with a dismal outcome. In conclusion, to determine COO both by IHC and GEP is the strongest outcome predictor to identify DLBCL patients with the worst outcome.

    Fulltekst (pdf)
    fulltext
  • 2.
    Andersson Evelönn, Emma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Köhn, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC)2016Inngår i: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, nr 8, s. 10219-10228Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Epigenetic alterations in the methylome have been associated with tumor development and progression in renal cell carcinoma (RCC). In this study, 45 tumor samples, 12 tumor-free kidney cortex tissues, and 24 peripheral blood samples from patients with clear cell RCC (ccRCC) were analyzed by genome-wide promoter-directed methylation arrays and related to clinicopathological parameters. Unsupervised hierarchical clustering separated the tumors into two distinct methylation groups (clusters A and B), where cluster B had higher average methylation and increased number of hypermethylated CpG sites (CpGs). Furthermore, tumors in cluster B had, compared with cluster A, a larger tumor diameter (p = 0.033), a higher morphologic grade (p < 0.001), a higher tumor-node-metastasis (TNM) stage (p < 0.001), and a worse prognosis (p = 0.005). Higher TNM stage was correlated to an increase in average methylation level (p = 0.003) and number of hypermethylated CpGs (p = 0.003), whereas a number of hypomethylated CpGs were mainly unchanged. However, the predicted age of the tumors based on methylation profile did not correlate with TNM stage, morphological grade, or methylation cluster. Differently methylated (DM) genes (n = 840) in ccRCC samples compared with tumor-free kidney cortex samples were predominantly hypermethylated and a high proportion were identified as polycomb target genes. The DM genes were overrepresented by transcription factors, ligands, and receptors, indicating functional alterations of significance for ccRCC progression. To conclude, increased number of hypermethylated genes was associated with increased TNM stage of the tumors. DNA methylation classification of ccRCC tumor samples at diagnosis can serve as a clinically applicable prognostic marker in ccRCC.

  • 3.
    Andersson Evelönn, Emma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Haider, Zahra
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Köhn, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    DNA methylation associates with survival in non-metastatic clear cell renal cell carcinoma2019Inngår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, artikkel-id 65Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype among renal cancer and is associated with poor prognosis if metastasized. Up to one third of patients with local disease at diagnosis will develop metastasis after nephrectomy, and there is a need for new molecular markers to identify patients with high risk of tumor progression. In the present study, we performed genome-wide promoter DNA methylation analysis at diagnosis to identify DNA methylation profiles associated with risk for progress.

    Method: Diagnostic tissue samples from 115 ccRCC patients were analysed by Illumina HumanMethylation450K arrays and methylation status of 155,931 promoter associated CpGs were related to genetic aberrations, gene expression and clinicopathological parameters.

    Results: The ccRCC samples separated into two clusters (cluster A/B) based on genome-wide promoter methylation status. The samples in these clusters differed in tumor diameter (p < 0.001), TNM stage (p < 0.001), morphological grade (p < 0.001), and patients outcome (5 year cancer specific survival (pCSS5yr) p < 0.001 and cumulative incidence of progress (pCIP5yr) p < 0.001. An integrated genomic and epigenomic analysis in the ccRCCs, revealed significant correlations between the total number of genetic aberrations and total number of hypermethylated CpGs (R = 0.435, p < 0.001), and predicted mitotic age (R = 0.407, p < 0.001). We identified a promoter methylation classifier (PMC) panel consisting of 172 differently methylated CpGs accompanying progress of disease. Classifying non-metastatic patients using the PMC panel showed that PMC high tumors had a worse prognosis compared with the PMC low tumors (pCIP5yr 38% vs. 8%, p = 0.001), which was confirmed in non-metastatic ccRCCs in the publically available TCGA-KIRC dataset (pCIP5yr 39% vs. 16%, p < 0.001).

    Conclusion: DNA methylation analysis at diagnosis in ccRCC has the potential to improve outcome-prediction in non-metastatic patients at diagnosis.

    Fulltekst (pdf)
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  • 4.
    Andersson, Ulrika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Dahlin, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Brannstrom, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Melin, B. S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Telomere length, allergies and risk of Glioma2017Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 19, nr S3, s. 23-23, artikkel-id P01.03Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: In glioma, a malignant brain tumour with poor prognosis, the etiology is largely unkown. Rare inherited syndromes, and high doses of ionising radiation are associated with increased risk of glioma. Common genetic variants have been associated with risk of glioma, and familial glioma have been associated with genetic variants in genes functionally important in telomere regulation (e.g. RTEL, TERT and POT1). The association between telomere length and risk of cancer is complex and seems to be tumour type dependent. Patients with asthma have significantly shorter telomeres than those of control subjects, and a protective effect has been observed with an inverse association with allergies and asthma and glioma risk. 

    Methods: We investigated population based glioma case-control series (431 cases and 672 controls) from Sweden at diagnosis with a quantitative PCR method for relative leukocyte telomere length measured in blood confirming with direct measurement of the association between telomere length and risk of glioma. We also explored the relationship between, age, gender, allergies and asthma, as these are established factors associated both with telomere length and glioma.

    Results: Longer relative leukocyte telomere length was significantly associated with increased risk of glioma, adjusting for age and gender (OR=2.23, CI: 1.11–4.47). As expected, for patients with allergies there was a protective effect with an inverse association with glioma risk, adjusting for age and gender (OR=0.64, CI; 0.48–0.85). Nevertheless, when analysing specific types of allergy, eczema (OR=0.66, CI; 0.41–1.08) and water eyes (OR=0.52, CI; 0.31–0.88) appeared to be more protective against glioma, compared to asthma (OR=0.92, CI; 0.59–1.41), and respiratory symptoms (OR=1.14, CI; 0.71–1.84) which showed no protective effect against glioma. Additionally adjusting for allergies did not markedly change the OR between relative leukocyte telomere length and glioma risk, indicating that the protective effect having allergies seems not to be coupled to telomere length. Conclusions: The adverse association of longer telomere and risk of glioma displays the complexity in understanding the biological role of telomere length and risk of developing cancer.

  • 5.
    Andersson, Ulrika
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Dahlin, Anna M.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Wibom, Carl
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Johansson, Gunnar
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bondy, Melissa L.
    Melin, Beatrice S.
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    The association between longer relative leukocyte telomere length and risk of glioma is independent of the potentially confounding factors allergy, BMI, and smoking2019Inngår i: Cancer Causes and Control, ISSN 0957-5243, E-ISSN 1573-7225, Vol. 30, nr 2, s. 177-185Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Previous studies have suggested an association between relative leukocyte telomere length (rLTL) and glioma risk. This association may be influenced by several factors, including allergies, BMI, and smoking. Previous studies have shown that individuals with asthma and allergy have shortened relative telomere length, and decreased risk of glioma. Though, the details and the interplay between rLTL, asthma and allergies, and glioma molecular phenotype is largely unknown. Methods: rLTL was measured by qPCR in a Swedish population-based glioma case–control cohort (421 cases and 671 controls). rLTL was related to glioma risk and health parameters associated with asthma and allergy, as well as molecular events in glioma including IDH1 mutation, 1p/19q co-deletion, and EGFR amplification. Results: Longer rLTL was associated with increased risk of glioma (OR = 1.16; 95% CI 1.02–1.31). Similar to previous reports, there was an inverse association between allergy and glioma risk. Specific, allergy symptoms including watery eyes was most strongly associated with glioma risk. High body mass index (BMI) a year prior diagnosis was significantly protective against glioma in our population. Adjusting for allergy, asthma, BMI, and smoking did not markedly change the association between longer rLTL and glioma risk. rLTL among cases was not associated with IDH1 mutation, 1p/19q co-deletion, or EGFR amplification, after adjusting for age at diagnosis and sex. Conclusions: In this Swedish glioma case–control cohort, we identified that long rLTL increases the risk of glioma, an association not confounded by allergy, BMI, or smoking. This highlights the complex interplay of the immune system, rLTL and cancer risk.

    Fulltekst (pdf)
    fulltext
  • 6.
    Andersson-Evelönn, Emma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Vidman, Linda
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Källberg, David
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Liu, Xijia
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Rydén, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Combining epigenetic and clinicopathological variables improves prognostic prediction in clear cell Renal Cell CarcinomaManuskript (preprint) (Annet vitenskapelig)
  • 7.
    Borssen, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Palmqvist, Lars
    Karrman, Kristina
    Abrahamsson, Jonas
    Behrendtz, Mikael
    Heldrup, Jesper
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia2013Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, nr 6, s. e65373-Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 8.
    Borssén, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Haider, Zahra
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Norén-Nyström, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    Schmiegelow, Kjeld
    Åsberg, Ann E.
    Kanerva, Jukka
    Madsen, Hans O.
    Marquart, Hanne
    Heyman, Mats
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Department of Paediatrics, University Hospital of Trondheim, Norway.
    DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia2016Inngår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, nr 7, s. 1185-1192Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background. Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >= 0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. Conclusions. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making.

    Fulltekst (pdf)
    fulltext
  • 9.
    Borssén, Magnus
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nordlund, Jessica
    Haider, Zahra
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Larsson, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Kanerva, Jukka
    Schmiegelow, Kjeld
    Flaegstad, Trond
    Jónsson, Ólafur Gísli
    Frost, Britt-Marie
    Palle, Josefine
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Heyman, Mats
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Lönnerholm, Gudmar
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia2018Inngår i: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, artikkel-id 31Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients.

    Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1-18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data.

    Results: Among the 137 patients that later relapsed, patients with a CIMP-profile (n = 42) at initial diagnosis had an inferior overall survival (pOS(5years) 33%) compared to CIMP+ patients (n = 95, pOS(5years) 65%) (p = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors.

    Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL.

    Fulltekst (pdf)
    fulltext
  • 10.
    Bovinder Ylitalo, Erik
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Thysell, Elin
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Jernberg, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Crnalic, Sead
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Ortopedi.
    Widmark, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Bergh, Anders
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wikström, Pernilla
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Integrated DNA methylation and gene expression analysis of molecular heterogeneity in prostate cancer bone metastasisManuskript (preprint) (Annet vitenskapelig)
  • 11.
    Degerman, Sofie
    et al.
    Umeå universitet, Medicinska fakulteten. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Borssen, Magnus
    Umeå universitet, Medicinska fakulteten. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    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 universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Senescence bypass and immortalization of T cell cultures are linked to stepwise DNA methylation changesManuskript (preprint) (Annet vitenskapelig)
  • 12.
    Degerman, Sofie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Domellöf, Magdalena
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Linder, Jan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Lundin, Mathias
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Haraldsson, Susann
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Elgh, Eva
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Long Leukocyte Telomere Length at Diagnosis Is a Risk Factor for Dementia Progression in Idiopathic Parkinsonism2014Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, nr 12, artikkel-id e113387Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 13.
    Degerman, Sofie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Josefsson, Maria
    Umeå universitet, Samhällsvetenskapliga fakulteten, Enheten för demografi och åldrandeforskning (CEDAR).
    Nordin Adolfsson, Annelie
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Wennstedt, Sigrid
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Haider, Zahra
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Pudas, Sara
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI). Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Adolfsson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Maintained memory in aging is associated with young epigenetic age2017Inngår i: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 55, s. 167-171Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Epigenetic alterations during aging have been proposed to contribute to decline in physical and cognitive functions, and accelerated epigenetic aging has been associated with disease and all-cause mortality later in life. In this study, we estimated epigenetic age dynamics in groups with different memory trajectories (maintained high performance, average decline, and accelerated decline) over a 15-year period. Epigenetic (DNA-methylation [DNAm]) age was assessed, and delta age (DNAm age - chronological age) was calculated in blood samples at baseline (age: 55-65 years) and 15 years later in 52 age- and gender-matched individuals from the Betula study in Sweden. A lower delta DNAm age was observed for those with maintained memory functions compared with those with average (p = 0.035) or accelerated decline (p = 0.037). Moreover, separate analyses revealed that DNAm age at follow-up, but not chronologic age, was a significant predictor of dementia (p = 0.019). Our findings suggest that young epigenetic age contributes to maintained memory in aging.

    Fulltekst (pdf)
    fulltext
  • 14.
    Degerman, Sofie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik. Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Siwicki, Jan Konrad
    Revie, John
    Borssen, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Evelönn, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Chrzanowska, Krystyna H.
    Ryden, Patrik
    Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Institutionen för matematik och matematisk statistik.
    Keith, W. Nicol
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias2014Inngår i: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, nr 7, s. 606-615Artikkel i tidsskrift (Fagfellevurdert)
    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.

    Fulltekst (pdf)
    fulltext
  • 15.
    Degerman, Sofie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Siwicki, Jan Konrad
    Department of Immunology, Maria Sklodowska-Curie memorial Cancer Centre and Institute of Oncology, 02-781 Warsaw, Poland.
    Osterman, Pia
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    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 universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Telomerase upregulation is a postcrisis event during senescence bypass and immortalization of two Nijmegen breakage syndrome T cell cultures2010Inngår i: Aging Cell, ISSN 1474-9718, E-ISSN 1474-9726, Vol. 9, s. 220-235Artikkel i tidsskrift (Fagfellevurdert)
    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.

  • 16.
    Degerman, Sofie
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Tumkur Sitaram, Raviprakash
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    The NBS1 gene is overexpressed and regulated by DJ-1 in clear cell renal cell carcinomaManuskript (preprint) (Annet vitenskapelig)
  • 17. Fogelstrand, Linda
    et al.
    Staffas, Anna
    Wasslavik, Carina
    Sjogren, Helene
    Soderhall, Stefan
    Frost, Britt-Marie
    Forestier, Erik
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Behrendtz, Mikael
    Heldrup, Jesper
    Karrman, Kristina
    Johansson, Bertil
    Heyman, Mats
    Abrahamsson, Jonas
    Palmqvist, Lars
    Prognostic Implications of Mutations in NOTCH1 and FBXW7 in Childhood T-ALL Treated According to the NOPHO ALL-1992 and ALL-2000 Protocols2014Inngår i: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 61, nr 3, s. 424-430Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.

    Procedure We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.

    Results Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P=0.14) or event-free survival (EFS) (P=0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.21.9 (mean +/- SEM), MYB 8.7 +/- 0.8 (mean +/- SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 +/- 0.7, MYB 5.1 +/- 1.2, P=0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P=0.02) and EFS (P=0.028) was seen.

    Conclusions Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated. Pediatr Blood Cancer 2014;61:424-430. (c) 2013 Wiley Periodicals, Inc.

  • 18. Garcia-Cisneros, A.
    et al.
    Perez-Portela, R.
    Almroth, B. C.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Palacin, C.
    Skold, H. Nilsson
    Long telomeres are associated with clonality in wild populations of the fissiparous starfish Coscinasterias tenuispina2015Inngår i: Heredity, ISSN 0018-067X, E-ISSN 1365-2540, Vol. 115, nr 5, s. 437-443Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Telomeres usually shorten during an organism's lifespan and have thus been used as an aging and health marker. When telomeres become sufficiently short, senescence is induced. The most common method of restoring telomere length is via telomerase reverse transcriptase activity, highly expressed during embryogenesis. However, although asexual reproduction from adult tissues has an important role in the life cycles of certain species, its effect on the aging and fitness of wild populations, as well as its implications for the long-term survival of populations with limited genetic variation, is largely unknown. Here we compare relative telomere length of 58 individuals from four populations of the asexually reproducing starfish Coscinasterias tenuispina. Additionally, 12 individuals were used to compare telomere lengths in regenerating and non-regenerating arms, in two different tissues (tube feet and pyloric cecum). The level of clonality was assessed by genotyping the populations based on 12 specific microsatellite loci and relative telomere length was measured via quantitative PCR. The results revealed significantly longer telomeres in Mediterranean populations than Atlantic ones as demonstrated by the Kruskal-Wallis test (K=24.17, significant value: P-value <0.001), with the former also characterized by higher levels of clonality derived from asexual reproduction. Telomeres were furthermore significantly longer in regenerating arms than in non-regenerating arms within individuals (pyloric cecum tissue: Mann-Whitney test, V=299, P-value <10(-6); and tube feet tissue Student's t=2.28, P-value = 0.029). Our study suggests that one of the mechanisms responsible for the long-term somatic maintenance and persistence of clonal populations is telomere elongation.

  • 19. Hagg, S.
    et al.
    Zhan, Y.
    Karlsson, R.
    Gerritsen, L.
    Ploner, A.
    van der Lee, S. J.
    Broer, L.
    Deelen, J.
    Marioni, R. E.
    Wong, A.
    Lundquist, Anders
    Umeå universitet, Samhällsvetenskapliga fakulteten, Handelshögskolan vid Umeå universitet, Statistik.
    Zhu, G.
    Hansell, N. K.
    Sillanpaa, E.
    Fedko, I. O.
    Amin, N. A.
    Beekman, M.
    de Craen, A. J. M.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Harris, S. E.
    Kan, K-J
    Martin-Ruiz, C. M.
    Montgomery, G. W.
    Adolfsson, Annelie N.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Reynolds, C. A.
    Samani, N. J.
    Suchiman, H. E. D.
    Viljanen, A.
    von Zglinicki, T.
    Wright, M. J.
    Hottenga, J-J
    Boomsma, D. I.
    Rantanen, T.
    Kaprio, J. A.
    Nyholt, D. R.
    Martin, N. G.
    Nyberg, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper. Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB). Umeå universitet, Medicinska fakulteten, Umeå centrum för funktionell hjärnavbildning (UFBI).
    Adolfsson, Rolf
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Kuh, D.
    Starr, J. M.
    Deary, I. J.
    Slagboom, P. E.
    van Duijn, C. M.
    Codd, V.
    Pedersen, N. L.
    Short telomere length is associated with impaired cognitive performance in European ancestry cohorts2017Inngår i: Translational Psychiatry, ISSN 2158-3188, E-ISSN 2158-3188, Vol. 7, artikkel-id e1100Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N = 17 052; mean age = 59.2 +/- 8.8 years) provided results for associations between qPCR-measuredTL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (beta = 0.051 per s. d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P = 0.0002), and MMSE (beta = 0.025; 95% CI: 0.002, 0.047; P = 0.03), and faster STROOP (beta = -0.053; 95% CI: -0.087, -0.018; P = 0.003). Effects for DSST were stronger in APOE epsilon 4 non-carriers (beta = 0.081; 95% CI: 0.045, 0.117; P = 1.0 x 10(-5)), whereas carriers performed better in STROOP (beta = -0.074; 95% CI: -0.140, -0.009; P = 0.03). Causal associations were found for STROOP only (beta = -0.598 per s. d.-increase of TL; 95% CI: -1.125, -0.072; P = 0.026), with a larger effect in epsilon 4-carriers (beta = -0.699; 95% CI: -1.330, -0.069; P = 0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE epsilon 4-carriers might be at differential risk.

    Fulltekst (pdf)
    fulltext
  • 20.
    Haider, Zahra
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Erlanson, Martin
    Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Noren-Nyström, Ulrika
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Epigenetic and genetic distinctions between T-cell acute lymphoblastic leukemia and lymphomaManuskript (preprint) (Annet vitenskapelig)
  • 21.
    Haider, Zahra
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Larsson, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Köhn, Linda
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi. Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper.
    Schmiegelow, Kjeld
    Flaegstad, Trond
    Kanerva, Jukka
    Heyman, Mats
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression2019Inngår i: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, nr 1, s. 311-324Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Classification of pediatric T‐cell acute lymphoblastic leukemia (T‐ALL) patients into CIMP (CpG Island Methylator Phenotype) subgroups has the potential to improve current risk stratification. To investigate the biology behind these CIMP subgroups, diagnostic samples from Nordic pediatric T‐ALL patients were characterized by genome‐wide methylation arrays, followed by targeted exome sequencing, telomere length measurement, and RNA sequencing. The CIMP subgroups did not correlate significantly with variations in epigenetic regulators. However, the CIMP+ subgroup, associated with better prognosis, showed indicators of longer replicative history, including shorter telomere length (P = 0.015) and older epigenetic (P < 0.001) and mitotic age (P < 0.001). Moreover, the CIMP+ subgroup had significantly higher expression of ANTP homeobox oncogenes, namely TLX3, HOXA9, HOXA10, and NKX2‐1, and novel genes in T‐ALL biology including PLCB4, PLXND1, and MYO18B. The CIMP− subgroup, with worse prognosis, was associated with higher expression of TAL1 along with frequent STIL‐TAL1 fusions (2/40 in CIMP+ vs 11/24 in CIMP−), as well as stronger expression of BEX1. Altogether, our findings suggest different routes for leukemogenic transformation in the T‐ALL CIMP subgroups, indicated by different replicative histories and distinct methylomic and transcriptomic profiles. These novel findings can lead to new therapeutic strategies.

    Fulltekst (pdf)
    fulltext
  • 22. Henckel, E.
    et al.
    Svenson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Nordlund, B.
    Berggren Broström, E.
    Hedlin, G.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bohlin, K.
    Telomere length was similar in school-age children with bronchopulmonary dysplasia and allergic asthma2018Inngår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 107, nr 8, s. 1395-1401Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aim: Inflammation is a major factor in the pathophysiology of bronchopulmonary dysplasia (BPD), and it contributes to accelerated telomere shortening and cellular ageing. This study aimed to determine its effect on telomere length and lung function in school-aged children born preterm with BPD.

    Methods: We examined 29 children with BPD, born preterm in Stockholm county 1998-99, along with 28 children with allergic asthma born at term matched for age and gender. At 10 years of age, we measured relative telomere length (RTL) in blood by quantitative polymerase chain reaction, lung function by spirometry and inflammation by fractional exhaled nitric oxide and blood cytokines.

    Results: RTL was not different in preterm born with BPD compared to term born children with asthma. The gender effect was strong in both groups; girls had significantly longer median RTL than boys (1.8 versus 1.5, p < 0.01). Short RTL was associated with low forced expiratory flow, also after adjusting for gender, but was not affected by severity of BPD or ongoing inflammation.

    Conclusion: Telomere length was similar in 10-year-old children born preterm with a history of BPD and term born children with allergic asthma. However, impaired lung function and male gender were associated wrth short telomeres.

  • 23. Henckel, Ewa
    et al.
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Haider, Zahra
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Kosma, Paraskevi
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Bohlin, Kajsa
    Hematopoietic cellular aging is not accelerated during the first 2 years of life in children born preterm2020Inngår i: Pediatric Research, ISSN 0031-3998, E-ISSN 1530-0447Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Prematurity in itself and exposure to neonatal intensive care triggers inflammatory processes and oxidative stress, leading to risk for disease later in life. The effects on cellular aging processes are incompletely understood.

    Methods: Relative telomere length (RTL) was measured by qPCR in this longitudinal cohort study with blood samples taken at birth and at 2 years of age from 60 children (16 preterm and 44 term). Viral respiratory infections the first year were evaluated. Epigenetic biological DNA methylation (DNAm) age was predicted based on methylation array data in 23 children (11 preterm and 12 term). RTL change/year and DNAm age change/year was compared in preterm and term during the 2 first years of life.

    Results: Preterm infants had longer telomeres than term born at birth and at 2 years of age, but no difference in telomere attrition rate could be detected. Predicted epigenetic DNAm age was younger in preterm infants, but rate of DNAm aging was similar in both groups.

    Conclusions: Despite early exposure to risk factors for accelerated cellular aging, children born preterm exhibited preserved telomeres. Stress during the neonatal intensive care period did not reflect accelerated epigenetic DNAm aging. Early-life aging was not explained by preterm birth.

    Impact: Preterm birth is associated with elevated disease risk later in life. Preterm children often suffer from inflammation early in life. Stress-related telomere erosion during neonatal intensive care has been proposed. Inflammation-accelerated biological aging in preterm is unknown. We find no accelerated aging due to prematurity or infections during the first 2 years of life.

  • 24. Hirvonen, Elina A. M.
    et al.
    Peuhkuri, Saara
    Norberg, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Hannula-Jouppi, Katariina
    Välimaa, Hannamari
    Kilpivaara, Outi
    Wartiovaara-Kautto, Ulla
    Characterization of an X-chromosome-linked telomere biology disorder in females with DKC1 mutation2019Inngår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 33, nr 1, s. 275-278Artikkel i tidsskrift (Fagfellevurdert)
  • 25.
    Kolan, Shrikant S
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Lidström, Tommy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Mediavilla, Tomás
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Dernstedt, Andy
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Björk, Karl
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Marcellino, Daniel
    Umeå universitet, Medicinska fakulteten, Institutionen för integrativ medicinsk biologi (IMB).
    Forsell, Mattias N. E.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Growth-inhibition of cell lines derived from B cell lymphomas through antagonism of serotonin receptor signaling2019Inngår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, artikkel-id 4276Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    A majority of lymphomas are derived from B cells and novel treatments are required to treat refractory disease. Neurotransmitters such as serotonin and dopamine influence activation of B cells and the effects of a selective serotonin 1A receptor (5HT1A) antagonist on growth of a number of B cell-derived lymphoma cell lines were investigated. We confirmed the expression of 5HT1A in human lymphoma tissue and in several well-defined experimental cell lines. We discovered that the pharmacological inhibition of 5HT1A led to the reduced proliferation of B cell-derived lymphoma cell lines together with DNA damage, ROS-independent caspase activation and apoptosis in a large fraction of cells. Residual live cells were found ‘locked’ in a non-proliferative state in which a selective transcriptional and translational shutdown of genes important for cell proliferation and metabolism occurred (e.g., AKT, GSK-3β, cMYC and p53). Strikingly, inhibition of 5HT1A regulated mitochondrial activity through a rapid reduction of mitochondrial membrane potential and reducing dehydrogenase activity. Collectively, our data suggest 5HT1A antagonism as a novel adjuvant to established cancer treatment regimens to further inhibit lymphoma growth.

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  • 26. Kostjukovits, Svetlana
    et al.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Pekkinen, Minna
    Klemetti, Paula
    Landfors, Mattias
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Taskinen, Mervi
    Makitie, Outi
    Decreased telomere length in children with cartilage-hair hypoplasia2017Inngår i: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 54, nr 5, s. 365-370Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background Cartilage-hair hypoplasia (CHH) is an autosomal recessive chondrodysplasia caused by RMRP (RNA component of mitochondrial RNA processing endoribonuclease) gene mutations. Manifestations include short stature, variable immunodeficiency, anaemia and increased risk of malignancies, all of which have been described also in telomere biology disorders. RMRP interacts with the telomerase RT (TERT) subunit, but the influence of RMRP mutations on telomere length is unknown. We measured relative telomere length (RTL) in patients with CHH, their first-degree relatives and healthy controls and correlated RTL with clinical and laboratory features. Methods The study cohort included 48 patients with CHH with homozygous (n=36) or compound heterozygous RMRP mutations (median age 38.2 years, range 6.0-70.8 years), 86 relatives (74 with a heterozygous RMRP mutation) and 94 unrelated healthy controls. We extracted DNA from peripheral blood, sequenced the RMRP gene and measured RTL by qPCR. Results Compared with age-matched and sex-matched healthy controls, median RTL was significantly shorter in patients with CHH (n=40 pairs, 1.05 vs 1.21, p=0.017), but not in mutation carriers (n=48 pairs, 1.16 vs 1.10, p=0.224). RTL correlated significantly with age in RMRP mutation carriers (r=-0.482, p < 0.001) and non-carriers (r=-0.498, p<0.001), but not in patients (r=-0.236, p=0.107). In particular children (< 18 years) with CHH had shorter telomeres than controls (median RTL 1.12 vs 1.26, p=0.008). In patients with CHH, RTL showed no correlation with genotype, clinical or laboratory characteristics. Conclusions Telomere length was decreased in children with CHH. We found no correlation between RTL and clinical or laboratory parameters.

  • 27.
    Mansouri, Larry
    et al.
    Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University; Uppsala, Sweden.
    Grabowski, Pawel
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Svenson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    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 universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Telomere length is a robust prognostic marker in early chronic lymphocytic leukemiaManuskript (preprint) (Annet vitenskapelig)
  • 28. Mansouri, Larry
    et al.
    Grabowski, Pawel
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Svenson, Ulrika
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Gunnarsson, Rebeqa
    Cahill, Nicola
    Smedby, Karin Ekstrom
    Geisler, Christian
    Juliusson, Gunnar
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Rosenquist, Richard
    Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients2013Inngår i: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 88, nr 8, s. 647-651Artikkel i tidsskrift (Fagfellevurdert)
  • 29.
    Norberg, Anna
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Rosén, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik. Umeå universitet, Medicinska fakulteten, Institutionen för strålningsvetenskaper, Onkologi.
    Raaschou-Jensen, Klas
    Kjeldsen, Lars
    Moilanen, Jukka S.
    Paulsson-Karisson, Ylva
    Baliakas, Panagiotis
    Lohi, Olli
    Ahmed, Aymen
    Kittang, Astrid O.
    Larsson, Pär
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Hultdin, Magnus
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Novel variants in Nordic patients referred for genetic testing of telomere-related disorders2018Inngår i: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, nr 6, s. 858-867Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders.

  • 30.
    Sitaram, Raviprakash T
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Ljungberg, Börje
    Umeå universitet, Medicinska fakulteten, Institutionen för kirurgisk och perioperativ vetenskap, Urologi och andrologi.
    Andersson, Emma
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Oji, Y
    Department of Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, Osaka, Japan.
    Sugiyama, H
    Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, Osaka, Japan.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Li, Ai-Hong
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Wilms' tumour 1 can suppress hTERT gene expression and telomerase activity in clear cell renal cell carcinoma via multiple pathways2010Inngår i: British Journal of Cancer, ISSN 0007-0920, E-ISSN 1532-1827, Vol. 103, nr 8, s. 1255-1262Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    BACKGROUND: Wilms' tumour 1 (WT1) gene was discovered as a tumour suppressor gene. Later findings have suggested that WT1 also can be oncogenic. This complexity is partly explained by the fact that WT1 has a number of target genes.

    METHOD: WT1 and its target gene human telomerase reverse transcriptase (hTERT) were analysed in clear cell renal cell carcinoma (ccRCC). In vitro experiments were performed to examine the functional link between WT1 and hTERT by overexpression of WT1 isoforms in the ccRCC cell line, TK-10.

    RESULTS: WT1 demonstrated lower RNA expression in ccRCC compared with renal cortical tissue, whereas hTERT was increased, showing a negative correlation between WT1 and hTERT (P=0.005). These findings were experimentally confirmed in vitro. The WT1 generated effect on hTERT promoter activity seemed complex, as several negative regulators of hTERT transcription, such as SMAD3, JUN (AP-1) and ETS1, were activated by WT1 overexpression. Downregulation of potential positive hTERT regulators, such as cMyc, AP-2α, AP-2γ, IRF1, NFX1 and GM-CSF, were also observed. Chromatin immunoprecipitation analysis verified WT1 binding to the hTERT, cMyc and SMAD3 promoters.

    CONCLUSION: The collected data strongly indicate multiple pathways for hTERT regulation by WT1 in ccRCC.

  • 31. Siwicki, Jan Konrad
    et al.
    Berglund, Mattias
    Rygier, Jolanta
    Pienkowska-Grela, Barbara
    Grygalewicz, Beata
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Golovleva, Irina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Chrzanowska, Krystyna H
    Lagercrantz, Svetlana
    Blennow, Elisabeth
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Larsson, Catharina
    Spontaneously immortalized human T lymphocytes develop gain of chromosomal region 2p13-24 as an early and common genetic event2004Inngår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 41, nr 2, s. 133-144Artikkel i tidsskrift (Fagfellevurdert)
  • 32.
    Siwicki, Jan Konrad
    et al.
    Department of Immunology, M. Skladowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Chrzanowska, Krystyna H
    Department of Medical Genetics, Childrens Memorial Health Institute, Warsaw, Poland.
    Roos, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Telomere maintenance and cell cycle regulation in spontaneously immortalized T-cell lines from Nijmegen breakage syndrome patients2003Inngår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 287, nr 1, s. 178-189Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Nijmegen breakage syndrome (NBS) is a rare genetic instability syndrome associated with a high incidence of lymphoid malignancies. The NBS1 protein has been implicated in telomere biology suggesting that cells from NBS patients might have deficient telomere maintenance capacity. In this study we characterized spontaneously immortalized T-cell lines derived from three NBS patients regarding growth characteristics, telomere biology, expression of cell-cycle regulators, and response to DNA damage to understand the role of NBS1 in the immortalization process. In all the NBS T-cell lines the acquisition of an immortal phenotype was associated with telomere length stabilization, high telomerase activity, and increased mRNA expression of the catalytic subunit of telomerase (hTERT), together with c-myc up-regulation. Our findings provide evidence that telomere length maintenance was intact in the T lymphocytes in the absence of a full-length NBS protein, presumably due to the presence of an alternatively transcribed NBS protein of 70 kDa. Normal protein expression patterns for pRb and p53 in all the immortal lines coincided with altered expression of some cell-cycle proteins as well as with an impaired G1/S arrest after gamma irradiation, despite a seemingly normal p53/p21 pathway. The here described, spontaneously immortalized NBS derived T-cell lines can be useful in future analysis of the biologic effects in the NBS.

  • 33. Trotta, Luca
    et al.
    Norberg, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Taskinen, Mervi
    Beziat, Vivien
    Degerman, Sofie
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Wartiovaara-Kautto, Ulla
    Valimaa, Hannamari
    Jahnukainen, Kirsi
    Casanova, Jean-Laurent
    Seppanen, Mikko
    Saarela, Janna
    Koskenvuo, Minna
    Martelius, Timi
    Diagnostics of rare disorders: whole-exome sequencing deciphering locus heterogeneity in telomere biology disorders2018Inngår i: Orphanet Journal of Rare Diseases, ISSN 1750-1172, E-ISSN 1750-1172, Vol. 13, artikkel-id 139Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKQ, the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs.

    Methods: Clinical sequencing was performed on a cohort of patients presenting with variable immune phenotypes lacking molecular diagnoses. Hypothesis-free whole-exome sequencing (WES) was selected in the absence of compelling diagnostic hints in patients with variable immunological and haematological conditions.

    Results: In four patients belonging to three families, we have detected five novel variants in known TBD-causing genes (DKC1, TERT and RTEL1). In addition to the molecular findings, they all presented shortened blood cell telomeres. These findings are consistent with the displayed TBD phenotypes, addressing towards the molecular diagnosis and subsequent clinical follow-up of the patients.

    Conclusions: Our results strongly support the utility of WES-based approaches for routine genetic diagnostics of TBD patients with heterogeneous or atypical clinical presentation who otherwise might remain undiagnosed.

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