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Lundmark, Anders
Publications (10 of 10) Show all publications
Gunnarsson, R., DiLorenzo, S., Lundin-Ström, K. B., Olsson, L., Biloglav, A., Lilljebjörn, H., . . . Johansson, B. (2018). Mutation, methylation, and gene expression profiles in dup(1q)-positive pediatric B-cell precursor acute lymphoblastic leukemia. Leukemia, 32(10), 2117-2125
Open this publication in new window or tab >>Mutation, methylation, and gene expression profiles in dup(1q)-positive pediatric B-cell precursor acute lymphoblastic leukemia
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2018 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, no 10, p. 2117-2125Article in journal (Refereed) Published
Abstract [en]

High-throughput sequencing was applied to investigate the mutation/methylation patterns on 1q and gene expression profiles in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) with/without (w/wo) dup(1q). Sequencing of the breakpoint regions and all exons on 1q in seven dup(1q)-positive cases revealed non-synonymous somatic single nucleotide variants (SNVs) in BLZF1, FMN2, KCNT2, LCE1C, NES, and PARP1. Deep sequencing of these in a validation cohort w (n = 17)/wo (n = 94) dup(1q) revealed similar SNV frequencies in the two groups (47% vs. 35%; P = 0.42). Only 0.6% of the 36,259 CpGs on 1q were differentially methylated between cases w (n = 14)/wo (n = 13) dup(1q). RNA sequencing of high hyperdiploid (HeH) and t(1;19)(q23;p13)-positive cases w (n = 14)/wo (n = 52) dup(1q) identified 252 and 424 differentially expressed genes, respectively; only seven overlapped. Of the overexpressed genes in the HeH and t(1;19) groups, 23 and 31%, respectively, mapped to 1q; 60-80% of these encode nucleic acid/protein binding factors or proteins with catalytic activity. We conclude that the pathogenetically important consequence of dup(1q) in BCP ALL is a gene-dosage effect, with the deregulated genes differing between genetic subtypes, but involving similar molecular functions, biological processes, and protein classes.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-367402 (URN)10.1038/s41375-018-0092-2 (DOI)000446171800003 ()29626196 (PubMedID)
Funder
Swedish Research Council, 2016-01084Swedish Cancer Society, CAN 2017/291Swedish Childhood Cancer Foundation, PR2015-0006
Available from: 2018-12-03 Created: 2018-12-03 Last updated: 2018-12-03Bibliographically approved
Lindqvist, C. M., Lundmark, A., Nordlund, J., Freyhult, E., Ekman, D., Almlöf, J. C., . . . Syvänen, A.-C. (2016). Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes. OncoTarget, 7(39), 64071-64088
Open this publication in new window or tab >>Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 39, p. 64071-64088Article in journal (Refereed) Published
Abstract [en]

To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency.

Keywords
acute lymphoblastic leukemia, targeted next generation sequencing, somatic mutation, relapse, clonal evolution
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-310028 (URN)10.18632/oncotarget.11773 (DOI)000387167800099 ()27590521 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RBc08-08Swedish Cancer Society, CAN 2013/504Swedish Childhood Cancer Foundation, PR2014-0100Swedish Research Council, C0524801Knut and Alice Wallenberg Foundation
Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2018-01-13Bibliographically approved
Wahlberg, P., Lundmark, A., Nordlund, J., Busche, S., Raine, A., Tandre, K., . . . Syvänen, A.-C. (2016). DNA methylome analysis of acute lymphoblastic leukemia cells reveals stochastic de novo DNA methylation in CpG islands. Epigenomics, 8(10), 1367-1387
Open this publication in new window or tab >>DNA methylome analysis of acute lymphoblastic leukemia cells reveals stochastic de novo DNA methylation in CpG islands
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2016 (English)In: Epigenomics, ISSN 1750-1911, Vol. 8, no 10, p. 1367-1387Article in journal (Refereed) Published
Abstract [en]

Aim: To identify regions of aberrant DNA methylation in acute lymphoblastic leukemia (ALL) cells of different subtypes on a genome-wide scale. Materials & methods: Whole-genome bisulfite sequencing (WGBS) was used to determine the DNA methylation levels in cells from four pediatric ALL patients of different subtypes. The findings were confirmed by 450k DNA methylation arrays in a large patient set. Results: Compared with mature B or T cells WGBS detected on average 82,000 differentially methylated regions per patient. Differentially methylated regions are enriched to CpG poor regions, active enhancers and transcriptional start sites. We also identified approximately 8000 CpG islands with variable intermediate DNA methylation that seems to occur as a result of stochastic de novo methylation. Conclusion: WGBS provides an unbiased view and novel insights into the DNA methylome of ALL cells.

Keywords
acute lymphoblastic leukemia, CpG islands, DNA methylation, epigenome, methylome, whole-genome bisulfite sequencing
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-308929 (URN)10.2217/epi-2016-0052 (DOI)000385653900006 ()27552300 (PubMedID)
Funder
Swedish Foundation for Strategic Research , RBc08-008Swedish Cancer Society, 140581Swedish Childhood Cancer Foundation, PR2014-0100Swedish Research Council, C0524801;259-2012-23Forte, Swedish Research Council for Health, Working Life and WelfareSwedish Research Council FormasVINNOVA
Available from: 2016-12-01 Created: 2016-12-01 Last updated: 2018-01-13Bibliographically approved
Almlöf, J., Lundmark, P., Lundmark, A., Ge, B., Pastinen, T., Goodall, A. H., . . . Syvänen, A.-C. (2014). Single nucleotide polymorphisms with cis-regulatory effects on long non-coding transcripts in human primary monocytes. PLoS ONE, 9(7), e102612
Open this publication in new window or tab >>Single nucleotide polymorphisms with cis-regulatory effects on long non-coding transcripts in human primary monocytes
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2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 7, p. e102612-Article in journal (Refereed) Published
Abstract [en]

We applied genome-wide allele-specific expression analysis of monocytes from 188 samples. Monocytes were purified from white blood cells of healthy blood donors to detect cis-acting genetic variation that regulates the expression of long non-coding RNAs. We analysed 8929 regions harboring genes for potential long non-coding RNA that were retrieved from data from the ENCODE project. Of these regions, 60% were annotated as intergenic, which implies that they do not overlap with protein-coding genes. Focusing on the intergenic regions, and using stringent analysis of the allele-specific expression data, we detected robust cis-regulatory SNPs in 258 out of 489 informative intergenic regions included in the analysis. The cis-regulatory SNPs that were significantly associated with allele-specific expression of long non-coding RNAs were enriched to enhancer regions marked for active or bivalent, poised chromatin by histone modifications. Out of the lncRNA regions regulated by cis-acting regulatory SNPs, 20% (n = 52) were co-regulated with the closest protein coding gene. We compared the identified cis-regulatory SNPs with those in the catalog of SNPs identified by genome-wide association studies of human diseases and traits. This comparison identified 32 SNPs in loci from genome-wide association studies that displayed a strong association signal with allele-specific expression of non-coding RNAs in monocytes, with p-values ranging from 6.7×10-7 to 9.5×10-89. The identified cis-regulatory SNPs are associated with diseases of the immune system, like multiple sclerosis and rheumatoid arthritis.

National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-230152 (URN)10.1371/journal.pone.0102612 (DOI)000339992400093 ()25025429 (PubMedID)
Available from: 2014-08-19 Created: 2014-08-19 Last updated: 2017-12-05Bibliographically approved
Deloukas, P., Kanoni, S., Willenborg, C., Farrall, M., Assimes, T. L., Thompson, J. R., . . . Samani, N. J. (2013). Large-scale association analysis identifies new risk loci for coronary artery disease. Nature Genetics, 45(1), 25-33
Open this publication in new window or tab >>Large-scale association analysis identifies new risk loci for coronary artery disease
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2013 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 45, no 1, p. 25-33Article in journal (Refereed) Published
Abstract [en]

Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r2 < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-188806 (URN)10.1038/ng.2480 (DOI)000312838800009 ()23202125 (PubMedID)
Available from: 2012-12-19 Created: 2012-12-19 Last updated: 2018-07-06Bibliographically approved
Nordlund, J., Milani, L., Lundmark, A., Lönnerholm, G. & Syvänen, A.-C. (2012). DNA Methylation Analysis of Bone Marrow Cells at Diagnosis of Acute Lymphoblastic Leukemia and at Remission. PLoS ONE, 7(4), e34513
Open this publication in new window or tab >>DNA Methylation Analysis of Bone Marrow Cells at Diagnosis of Acute Lymphoblastic Leukemia and at Remission
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 4, p. e34513-Article in journal (Refereed) Published
Abstract [en]

To detect genes with CpG sites that display methylation patterns that are characteristic of acute lymphoblastic leukemia (ALL) cells, we compared the methylation patterns of cells taken at diagnosis from 20 patients with pediatric ALL to the methylation patterns in mononuclear cells from bone marrow of the same patients during remission and in non-leukemic control cells from bone marrow or blood. Using a custom-designed assay, we measured the methylation levels of 1,320 CpG sites in regulatory regions of 413 genes that were analyzed because they display allele-specific gene expression (ASE) in ALL cells. The rationale for our selection of CpG sites was that ASE could be the result of allele-specific methylation in the promoter regions of the genes. We found that the ALL cells had methylation profiles that allowed distinction between ALL cells and control cells. Using stringent criteria for calling differential methylation, we identified 28 CpG sites in 24 genes with recurrent differences in their methylation levels between ALL cells and control cells. Twenty of the differentially methylated genes were hypermethylated in the ALL cells, and as many as nine of them (AMICA1, CPNE7, CR1, DBC1, EYA4, LGALS8, RYR3, UQCRFS1, WDR35) have functions in cell signaling and/or apoptosis. The methylation levels of a subset of the genes were consistent with an inverse relationship with the mRNA expression levels in a large number of ALL cells from published data sets, supporting a potential biological effect of the methylation signatures and their application for diagnostic purposes.

National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-178755 (URN)10.1371/journal.pone.0034513 (DOI)000305012700038 ()22493696 (PubMedID)
Available from: 2012-08-01 Created: 2012-08-01 Last updated: 2017-12-07Bibliographically approved
Almlöf, J. C., Lundmark, P., Lundmark, A., Ge, B., Maouche, S., Göring, H. H., . . . Syvänen, A.-C. (2012). Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression. PLoS ONE, 7(12), e52260
Open this publication in new window or tab >>Powerful Identification of Cis-regulatory SNPs in Human Primary Monocytes Using Allele-Specific Gene Expression
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2012 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 7, no 12, p. e52260-Article in journal (Refereed) Published
Abstract [en]

A large number of genome-wide association studies have been performed during the past five years to identify associations between SNPs and human complex diseases and traits. The assignment of a functional role for the identified disease-associated SNP is not straight-forward. Genome-wide expression quantitative trait locus (eQTL) analysis is frequently used as the initial step to define a function while allele-specific gene expression (ASE) analysis has not yet gained a wide-spread use in disease mapping studies. We compared the power to identify cis-acting regulatory SNPs (cis-rSNPs) by genome-wide allele-specific gene expression (ASE) analysis with that of traditional expression quantitative trait locus (eQTL) mapping. Our study included 395 healthy blood donors for whom global gene expression profiles in circulating monocytes were determined by Illumina BeadArrays. ASE was assessed in a subset of these monocytes from 188 donors by quantitative genotyping of mRNA using a genome-wide panel of SNP markers. The performance of the two methods for detecting cis-rSNPs was evaluated by comparing associations between SNP genotypes and gene expression levels in sample sets of varying size. We found that up to 8-fold more samples are required for eQTL mapping to reach the same statistical power as that obtained by ASE analysis for the same rSNPs. The performance of ASE is insensitive to SNPs with low minor allele frequencies and detects a larger number of significantly associated rSNPs using the same sample size as eQTL mapping. An unequivocal conclusion from our comparison is that ASE analysis is more sensitive for detecting cis-rSNPs than standard eQTL mapping. Our study shows the potential of ASE mapping in tissue samples and primary cells which are difficult to obtain in large numbers.

Keywords
messenger RNA, allele specific gene expression analysis, article, blood donor, DNA flanking region, gene expression, gene frequency, gene mapping, genetic analysis, genetic association, genotype, genotyping expression analysis, human, human cell, intermethod comparison, monocyte, quantitative trait locus mapping, sample size, single nucleotide polymorphism
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-195164 (URN)10.1371/journal.pone.0052260 (DOI)000313618800062 ()
Available from: 2013-02-22 Created: 2013-02-21 Last updated: 2017-12-06Bibliographically approved
Milani, L., Lundmark, A., Kiialainen, A., Nordlund, J., Flaegstad, T., Forestier, E., . . . Syvänen, A.-C. (2010). DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia. Blood, 115(6), 1214-1225
Open this publication in new window or tab >>DNA methylation for subtype classification and prediction of treatment outcome in patients with childhood acute lymphoblastic leukemia
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2010 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 115, no 6, p. 1214-1225Article in journal (Refereed) Published
Abstract [en]

Despite improvements in the prognosis of childhood acute lymphoblastic leukemia (ALL), subgroups of patients would benefit from alternative treatment approaches. Our aim was to identify genes with DNA methylation profiles that could identify such groups. We determined the methylation levels of 1320 CpG sites in regulatory regions of 416 genes in cells from 401 children diagnosed with ALL. Hierarchical clustering of 300 CpG sites distinguished between T-lineage ALL and B-cell precursor (BCP) ALL and between the main cytogenetic subtypes of BCP ALL. It also stratified patients with high hyperdiploidy and t(12;21) ALL into 2 subgroups with different probability of relapse. By using supervised learning, we constructed multivariate classifiers by external cross-validation procedures. We identified 40 genes that consistently contributed to accurate discrimination between the main subtypes of BCP ALL and gene sets that discriminated between subtypes of ALL and between ALL and controls in pairwise classification analyses. We also identified 20 individual genes with DNA methylation levels that predicted relapse of leukemia. Thus, methylation analysis should be explored as a method to improve stratification of ALL patients. The genes highlighted in our study are not enriched to specific pathways, but the gene expression levels are inversely correlated to the methylation levels.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-120571 (URN)10.1182/blood-2009-04-214668 (DOI)000274431400016 ()19965625 (PubMedID)
Available from: 2010-03-15 Created: 2010-03-15 Last updated: 2017-12-12Bibliographically approved
Milani, L., Lundmark, A., Nordlund, J., Kiialainen, A., Flaegstad, T., Jonmundsson, G., . . . Syvänen, A.-C. (2009). Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation. Genome Research, 19(1), 1-11
Open this publication in new window or tab >>Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation
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2009 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 19, no 1, p. 1-11Article in journal (Refereed) Published
Abstract [en]

To identify genes that are regulated by cis-acting functional elements in acute lymphoblastic leukemia (ALL) we determined the allele-specific expression (ASE) levels of 2, 529 genes by genotyping a genome-wide panel of single nucleotide polymorphisms in RNA and DNA from bone marrow and blood samples of 197 children with ALL. Using a reproducible, quantitative genotyping method and stringent criteria for scoring ASE, we found that 16% of the analyzed genes display ASE in multiple ALL cell samples. For most of the genes, the level of ASE varied largely between the samples, from 1.4-fold overexpression of one allele to apparent monoallelic expression. For genes exhibiting ASE, 55% displayed bidirectional ASE in which overexpression of either of the two SNP alleles occurred. For bidirectional ASE we also observed overall higher levels of ASE and correlation with the methylation level of these sites. Our results demonstrate that CpG site methylation is one of the factors that regulates gene expression in ALL cells.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-98392 (URN)10.1101/gr.083931.108 (DOI)000262200000001 ()18997001 (PubMedID)
Available from: 2009-02-20 Created: 2009-02-20 Last updated: 2017-12-13Bibliographically approved
Nordlund, J., Marincevic-Zuniga, Y., Cavelier, L., Raine, A., Martin, T., Lundmark, A., . . . Syvänen, A.-C.Refined detection and phasing of structural aberrations in pediatric acute lymphoblastic leukemia with linked-read whole genome sequencing.
Open this publication in new window or tab >>Refined detection and phasing of structural aberrations in pediatric acute lymphoblastic leukemia with linked-read whole genome sequencing
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(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology Medical Genetics
Research subject
Medical Genetics; Medical Science
Identifiers
urn:nbn:se:uu:diva-344007 (URN)
Available from: 2018-03-28 Created: 2018-03-28 Last updated: 2018-04-02
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