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Landfors, Mattias
Publications (10 of 20) Show all publications
Haider, Z., Larsson, P., Landfors, M., Köhn, L., Schmiegelow, K., Flaegstad, T., . . . Degerman, S. (2019). An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression. Cancer Medicine, 8(1), 311-324
Open this publication in new window or tab >>An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression
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2019 (English)In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, no 1, p. 311-324Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
BEX1, DNA methylation, HOXA, pediatric acute lymphoblastic leukemia, TAL1
National Category
Cancer and Oncology Hematology Pediatrics Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-156637 (URN)10.1002/cam4.1917 (DOI)000456858100032 ()30575306 (PubMedID)
Funder
The Kempe FoundationsSwedish Childhood Cancer FoundationVästerbotten County CouncilSwedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-02-20Bibliographically approved
Andersson-Evelönn, E., Landfors, M., Haider, Z., Köhn, L., Ljungberg, B., Roos, G. & Degerman, S. (2019). DNA methylation associates with survival in non-metastatic clear cell renal cell carcinoma. BMC Cancer, 19, Article ID 65.
Open this publication in new window or tab >>DNA methylation associates with survival in non-metastatic clear cell renal cell carcinoma
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2019 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 19, article id 65Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BioMed Central, 2019
Keywords
Clear cell renal cell carcinoma, DNA methylation, Prognosis, Genetic
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-155957 (URN)10.1186/s12885-019-5291-3 (DOI)000455576500013 ()30642274 (PubMedID)
Funder
The Kempe FoundationsSwedish Cancer SocietyVästerbotten County Council
Available from: 2019-02-08 Created: 2019-02-08 Last updated: 2019-02-08Bibliographically approved
Borssén, M., Nordlund, J., Haider, Z., Landfors, M., Larsson, P., Kanerva, J., . . . Degerman, S. (2018). DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia. Clinical Epigenetics, 10, Article ID 31.
Open this publication in new window or tab >>DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia
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2018 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 31Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
DNA methylation, BCP-ALL, prognosis, CIMP, relapse, risk stratification
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-146216 (URN)10.1186/s13148-018-0466-3 (DOI)000427080200001 ()29515676 (PubMedID)
Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2019-02-20Bibliographically approved
Kostjukovits, S., Degerman, S., Pekkinen, M., Klemetti, P., Landfors, M., Roos, G., . . . Makitie, O. (2017). Decreased telomere length in children with cartilage-hair hypoplasia. Journal of Medical Genetics, 54(5), 365-370
Open this publication in new window or tab >>Decreased telomere length in children with cartilage-hair hypoplasia
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2017 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 54, no 5, p. 365-370Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
BMJ PUBLISHING GROUP, 2017
National Category
Medical Genetics Clinical Laboratory Medicine
Identifiers
urn:nbn:se:umu:diva-136203 (URN)10.1136/jmedgenet-2016-104279 (DOI)000400022200009 ()27986801 (PubMedID)
Available from: 2017-07-03 Created: 2017-07-03 Last updated: 2018-06-09Bibliographically approved
Degerman, S., Josefsson, M., Nordin Adolfsson, A., Wennstedt, S., Landfors, M., Haider, Z., . . . Adolfsson, R. (2017). Maintained memory in aging is associated with young epigenetic age. Neurobiology of Aging, 55, 167-171
Open this publication in new window or tab >>Maintained memory in aging is associated with young epigenetic age
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2017 (English)In: Neurobiology of Aging, ISSN 0197-4580, E-ISSN 1558-1497, Vol. 55, p. 167-171Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
Elsevier, 2017
National Category
Other Basic Medicine
Identifiers
urn:nbn:se:umu:diva-132221 (URN)10.1016/j.neurobiolaging.2017.02.009 (DOI)000405068100018 ()28292535 (PubMedID)
Available from: 2017-03-07 Created: 2017-03-07 Last updated: 2019-05-10Bibliographically approved
Borssén, M., Haider, Z., Landfors, M., Norén-Nyström, U., Schmiegelow, K., Åsberg, A. E., . . . Degerman, S. (2016). DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia. Pediatric Blood & Cancer, 63(7), 1185-1192
Open this publication in new window or tab >>DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia
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2016 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 7, p. 1185-1192Article in journal (Refereed) Published
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.

Keywords
childhood leukemia, DNA methylation, MRD, prognosis, T-ALL, WBC
National Category
Cancer and Oncology Hematology Pediatrics
Identifiers
urn:nbn:se:umu:diva-124837 (URN)10.1002/pbc.25958 (DOI)000380105400008 ()26928953 (PubMedID)
Available from: 2016-10-03 Created: 2016-08-26 Last updated: 2019-05-10Bibliographically approved
Evelönn, E. A., Degerman, S., Köhn, L., Landfors, M., Ljungberg, B. & Roos, G. (2016). DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC). Tumor Biology, 37(8), 10219-10228
Open this publication in new window or tab >>DNA methylation status defines clinicopathological parameters including survival for patients with clear cell renal cell carcinoma (ccRCC)
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2016 (English)In: Tumor Biology, ISSN 1010-4283, E-ISSN 1423-0380, Vol. 37, no 8, p. 10219-10228Article in journal (Refereed) Published
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.

Keywords
Clear cell renal cell carcinoma, DNA methylation, Survival, Predicted age, Polycomb target genes
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-126325 (URN)10.1007/s13277-016-4893-5 (DOI)000382672900022 ()26831665 (PubMedID)
Available from: 2016-10-27 Created: 2016-10-03 Last updated: 2018-06-09Bibliographically approved
Degerman, S., Landfors, M., Siwicki, J. K., Revie, J., Borssen, M., Evelönn, E., . . . Roos, G. (2014). Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias. Neoplasia, 16(7), 606-615
Open this publication in new window or tab >>Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias
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2014 (English)In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, no 7, p. 606-615Article in journal (Refereed) Published
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.

National Category
Cancer and Oncology Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-93242 (URN)10.1016/j.neo.2014.07.001 (DOI)000340553900006 ()
Funder
Swedish Research Council, Dnr 340-2013-5185EU, FP7, Seventh Framework Programme, 200950
Available from: 2014-12-22 Created: 2014-09-15 Last updated: 2018-06-07Bibliographically approved
Degerman, S., Domellöf, M., Landfors, M., Linder, J., Lundin, M., Haraldsson, S., . . . Forsgren, L. (2014). Long Leukocyte Telomere Length at Diagnosis Is a Risk Factor for Dementia Progression in Idiopathic Parkinsonism. PLoS ONE, 9(12), Article ID e113387.
Open this publication in new window or tab >>Long Leukocyte Telomere Length at Diagnosis Is a Risk Factor for Dementia Progression in Idiopathic Parkinsonism
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 12, article id e113387Article in journal (Refereed) Published
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.

National Category
Basic Medicine Clinical Medicine
Identifiers
urn:nbn:se:umu:diva-99223 (URN)10.1371/journal.pone.0113387 (DOI)000346375400009 ()
Available from: 2015-04-20 Created: 2015-02-04 Last updated: 2018-06-07Bibliographically approved
Landfors, M. (2012). Normalization and analysis of high-dimensional genomics data. (Doctoral dissertation). Umeå: Umeå Universitet
Open this publication in new window or tab >>Normalization and analysis of high-dimensional genomics data
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In the middle of the 1990’s the microarray technology was introduced. The technology allowed for genome wide analysis of gene expression in one experiment. Since its introduction similar high through-put methods have been developed in other fields of molecular biology. These high through-put methods provide measurements for hundred up to millions of variables in a single experiment and a rigorous data analysis is necessary in order to answer the underlying biological questions.

Further complications arise in data analysis as technological variation is introduced in the data, due to the complexity of the experimental procedures in these experiments. This technological variation needs to be removed in order to draw relevant biological conclusions from the data. The process of removing the technical variation is referred to as normalization or pre-processing. During the last decade a large number of normalization and data analysis methods have been proposed.

In this thesis, data from two types of high through-put methods are used to evaluate the effect pre-processing methods have on further analyzes. In areas where problems in current methods are identified, novel normalization methods are proposed. The evaluations of known and novel methods are performed on simulated data, real data and data from an in-house produced spike-in experiment.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2012. p. 43
Keywords
normalization, pre-processing, microarray, downstream analysis, evaluation, sensitivity, bias, genomics data, gene expression, spike-in data, ChIP-chip
National Category
Bioinformatics and Systems Biology Probability Theory and Statistics
Research subject
Mathematical Statistics
Identifiers
urn:nbn:se:umu:diva-53486 (URN)978-91-7459-402-7 (ISBN)
Public defence
2012-04-20, MA121, Mit-huset, Umeå Universitet, Umeå, 19:25 (English)
Opponent
Supervisors
Available from: 2012-03-30 Created: 2012-03-28 Last updated: 2018-06-08Bibliographically approved
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