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Berglund, Eva Caroline
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Marincevic-Zuniga, Y., Dahlberg, J., Nilsson, S., Raine, A., Nystedt, S., Lindqvist, C. M., . . . Syvänen, A.-C. (2017). Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles. Journal of Hematology & Oncology, 10, Article ID 148.
Öppna denna publikation i ny flik eller fönster >>Transcriptome sequencing in pediatric acute lymphoblastic leukemia identifies fusion genes associated with distinct DNA methylation profiles
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2017 (Engelska)Ingår i: Journal of Hematology & Oncology, ISSN 1756-8722, E-ISSN 1756-8722, Vol. 10, artikel-id 148Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Structural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL). In this study, we performed transcriptome sequencing of 134 primary ALL patient samples to comprehensively detect fusion transcripts. Methods: We combined fusion gene detection with genome-wide DNA methylation analysis, gene expression profiling, and targeted sequencing to determine molecular signatures of emerging ALL subtypes. Results: We identified 64 unique fusion events distributed among 80 individual patients, of which over 50% have not previously been reported in ALL. Although the majority of the fusion genes were found only in a single patient, we identified several recurrent fusion gene families defined by promiscuous fusion gene partners, such as ETV6, RUNX1, PAX5, and ZNF384, or recurrent fusion genes, such as DUX4-IGH. Our data show that patients harboring these fusion genes displayed characteristic genome-wide DNA methylation and gene expression signatures in addition to distinct patterns in single nucleotide variants and recurrent copy number alterations. Conclusion: Our study delineates the fusion gene landscape in pediatric ALL, including both known and novel fusion genes, and highlights fusion gene families with shared molecular etiologies, which may provide additional information for prognosis and therapeutic options in the future.

Nyckelord
Pediatric acute lymphoblastic leukemia, RNA sequencing, Fusion genes, BCP-ALL, T-ALL, Translocation
Nationell ämneskategori
Cancer och onkologi Pediatrik
Identifikatorer
urn:nbn:se:uu:diva-332658 (URN)10.1186/s13045-017-0515-y (DOI)000408001300001 ()28806978 (PubMedID)
Forskningsfinansiär
Stiftelsen för strategisk forskning (SSF), RBc08-008Cancerfonden, 130440, 160711Barncancerfonden, 11098Vetenskapsrådet, C0524801, 2016-03691_3
Anmärkning

De 2 sista författarna delar sistaförfattarskapet.

Tillgänglig från: 2017-10-31 Skapad: 2017-10-31 Senast uppdaterad: 2019-10-23Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>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 (Engelska)Ingår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 39, s. 64071-64088Artikel i tidskrift (Refereegranskat) 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.

Nyckelord
acute lymphoblastic leukemia, targeted next generation sequencing, somatic mutation, relapse, clonal evolution
Nationell ämneskategori
Cancer och onkologi Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-310028 (URN)10.18632/oncotarget.11773 (DOI)000387167800099 ()27590521 (PubMedID)
Forskningsfinansiär
Stiftelsen för strategisk forskning (SSF), RBc08-08Cancerfonden, CAN 2013/504Barncancerfonden, PR2014-0100Vetenskapsrådet, C0524801Knut och Alice Wallenbergs Stiftelse
Tillgänglig från: 2016-12-12 Skapad: 2016-12-09 Senast uppdaterad: 2019-10-23Bibliografiskt granskad
Bahl, A., Pöllänen, E., Ismail, K., Sipilä, S., Mikkola, T. M., Berglund, E. C., . . . Ollikainen, M. (2015). Hormone Replacement Therapy Associated White Blood Cell DNA Methylation and Gene Expression are Associated With Within-Pair Differences of Body Adiposity and Bone Mass. Twin Research and Human Genetics, 18(6), 647-661
Öppna denna publikation i ny flik eller fönster >>Hormone Replacement Therapy Associated White Blood Cell DNA Methylation and Gene Expression are Associated With Within-Pair Differences of Body Adiposity and Bone Mass
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2015 (Engelska)Ingår i: Twin Research and Human Genetics, ISSN 1832-4274, E-ISSN 1839-2628, Vol. 18, nr 6, s. 647-661Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The loss of estrogen during menopause causes changes in the female body, with wide-ranging effects on health. Estrogen-containing hormone replacement therapy (HRT) leads to a relief of typical menopausal symptoms, benefits bone and muscle health, and is associated with tissue-specific gene expression profiles. As gene expression is controlled by epigenetic factors (including DNA methylation), many of which are environmentally sensitive, it is plausible that at least part of the HRT-associated gene expression is due to changes in DNA methylation profile. We investigated genome-wide DNA methylation and gene expression patterns of white blood cells (WBCs) and their associations with body composition, including muscle and bone measures of monozygotic (MZ) female twin pairs discordant for HRT. We identified 7,855 nominally significant differentially methylated regions (DMRs) associated with 4,044 genes. Of the genes with DMRs, five (ACBA1, CCL5, FASLG, PPP2R2B, and UHRF1) were also differentially expressed. All have been previously associated with HRT or estrogenic regulation, but not with HRT-associated DNA methylation. All five genes were associated with bone mineral content (BMC), and ABCA1, FASLG, and UHRF1 were also associated with body adiposity. Our study is the first to show that HRT associates with genome-wide DNA methylation alterations in WBCs. Moreover, we show that five differentially expressed genes with DMRs associate with clinical measures, including body fat percentage, lean body mass, bone mass, and blood lipids. Our results indicate that at least part of the known beneficial HRT effects on body composition and bone mass may be regulated by DNA methylation associated alterations in gene expression in circulating WBCs.

Nationell ämneskategori
Medicinsk genetik
Identifikatorer
urn:nbn:se:uu:diva-273809 (URN)10.1017/thg.2015.82 (DOI)000367159000004 ()26678050 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, E0226301 C0524801Cancerfonden, 140581Barncancerfonden, PR2014-0100Stiftelsen för strategisk forskning (SSF), RBc08-008
Tillgänglig från: 2016-01-18 Skapad: 2016-01-18 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
Lindqvist, C. M., Nordlund, J., Ekman, D., Johansson, A., Moghadam, B. T., Raine, A., . . . Berglund, E. C. (2015). The Mutational Landscape in Pediatric Acute Lymphoblastic Leukemia Deciphered by Whole Genome Sequencing. Human Mutation, 36(1), 118-128
Öppna denna publikation i ny flik eller fönster >>The Mutational Landscape in Pediatric Acute Lymphoblastic Leukemia Deciphered by Whole Genome Sequencing
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2015 (Engelska)Ingår i: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 36, nr 1, s. 118-128Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Genomic characterization of pediatric acute lymphoblastic leukemia (ALL) has identified distinct patterns of genes and pathways altered in patients with well-defined genetic aberrations. To extend the spectrum of known somatic variants in ALL, we performed whole genome and transcriptome sequencing of three B-cell precursor patients, of which one carried the t(12;21)ETV6-RUNX1 translocation and two lacked a known primary genetic aberration, and one T-ALL patient. We found that each patient had a unique genome, with a combination of well-known and previously undetected genomic aberrations. By targeted sequencing in 168 patients, we identified KMT2D and KIF1B as novel putative driver genes. We also identified a putative regulatory non-coding variant that coincided with overexpression of the growth factor MDK. Our results contribute to an increased understanding of the biological mechanisms that lead to ALL and suggest that regulatory variants may be more important for cancer development than recognized to date. The heterogeneity of the genetic aberrations in ALL renders whole genome sequencing particularly well suited for analysis of somatic variants in both research and diagnostic applications.

Nationell ämneskategori
Medicinsk genetik Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-238183 (URN)10.1002/humu.22719 (DOI)000347076700016 ()25355294 (PubMedID)
Tillgänglig från: 2014-12-10 Skapad: 2014-12-10 Senast uppdaterad: 2019-10-23Bibliografiskt granskad
Guy, L., Nystedt, B., Toft, C., Zaremba-Niedzwiedzka, K., Berglund, E. C., Granberg, F., . . . Andersson, S. G. E. (2013). A Gene Transfer Agent and a Dynamic Repertoire of Secretion Systems Hold the Keys to the Explosive Radiation of the Emerging Pathogen Bartonella. PLOS Genetics, 9(3), e1003393
Öppna denna publikation i ny flik eller fönster >>A Gene Transfer Agent and a Dynamic Repertoire of Secretion Systems Hold the Keys to the Explosive Radiation of the Emerging Pathogen Bartonella
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2013 (Engelska)Ingår i: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, nr 3, s. e1003393-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Gene transfer agents (GTAs) randomly transfer short fragments of a bacterial genome. A novel putative GTA was recently discovered in the mouse-infecting bacterium Bartonella grahamii. Although GTAs are widespread in phylogenetically diverse bacteria, their role in evolution is largely unknown. Here, we present a comparative analysis of 16 Bartonella genomes ranging from 1.4 to 2.6 Mb in size, including six novel genomes from Bartonella isolated from a cow, two moose, two dogs, and a kangaroo. A phylogenetic tree inferred from 428 orthologous core genes indicates that the deadly human pathogen B. bacilliformis is related to the ruminant-adapted clade, rather than being the earliest diverging species in the genus as previously thought. A gene flux analysis identified 12 genes for a GTA and a phage-derived origin of replication as the most conserved innovations. These are located in a region of a few hundred kb that also contains 8 insertions of gene clusters for type III, IV, and V secretion systems, and genes for putatively secreted molecules such as cholera-like toxins. The phylogenies indicate a recent transfer of seven genes in the virB gene cluster for a type IV secretion system from a catadapted B. henselae to a dog-adapted B. vinsonii strain. We show that the B. henselae GTA is functional and can transfer genes in vitro. We suggest that the maintenance of the GTA is driven by selection to increase the likelihood of horizontal gene transfer and argue that this process is beneficial at the population level, by facilitating adaptive evolution of the host-adaptation systems and thereby expansion of the host range size. The process counters gene loss and forces all cells to contribute to the production of the GTA and the secreted molecules. The results advance our understanding of the role that GTAs play for the evolution of bacterial genomes.

Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:uu:diva-199485 (URN)10.1371/journal.pgen.1003393 (DOI)000316866700064 ()
Tillgänglig från: 2013-05-07 Skapad: 2013-05-06 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Berglund, E. C., Lindqvist, C. M., Hayat, S., Overnäs, E., Henriksson, N., Nordlund, J., . . . Syvänen, A.-C. (2013). Accurate detection of subclonal single nucleotide variants in whole genome amplified and pooled cancer samples using HaloPlex target enrichment. BMC Genomics, 14(1), 856
Öppna denna publikation i ny flik eller fönster >>Accurate detection of subclonal single nucleotide variants in whole genome amplified and pooled cancer samples using HaloPlex target enrichment
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2013 (Engelska)Ingår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 14, nr 1, s. 856-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND:

Target enrichment and resequencing is a widely used approach for identification of cancer genes and genetic variants associated with diseases. Although cost effective compared to whole genome sequencing, analysis of many samples constitutes a significant cost, which could be reduced by pooling samples before capture. Another limitation to the number of cancer samples that can be analyzed is often the amount of available tumor DNA. We evaluated the performance of whole genome amplified DNA and the power to detect subclonal somatic single nucleotide variants in non-indexed pools of cancer samples using the HaloPlex technology for target enrichment and next generation sequencing.

RESULTS:

We captured a set of 1528 putative somatic single nucleotide variants and germline SNPs, which were identified by whole genome sequencing, with the HaloPlex technology and sequenced to a depth of 792--1752. We found that the allele fractions of the analyzed variants are well preserved during whole genome amplification and that capture specificity or variant calling is not affected. We detected a large majority of the known single nucleotide variants present uniquely in one sample with allele fractions as low as 0.1 in non-indexed pools of up to ten samples. We also identified and experimentally validated six novel variants in the samples included in the pools.

CONCLUSION:

Our work demonstrates that whole genome amplified DNA can be used for target enrichment equally well as genomic DNA and that accurate variant detection is possible in non-indexed pools of cancer samples. These findings show that analysis of a large number of samples is feasible at low cost, even when only small amounts of DNA is available, and thereby significantly increases the chances of indentifying recurrent mutations in cancer samples.

Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-212775 (URN)10.1186/1471-2164-14-856 (DOI)000328647700003 ()24314227 (PubMedID)
Forskningsfinansiär
Cancerfonden, CAN2010/592EU, Europeiska forskningsrådet, 262055Stiftelsen för strategisk forskning (SSF), RBc08-008Vetenskapsrådet, 90559401
Anmärkning

De två första författarna delar förstaförfattarskapet.

Tillgänglig från: 2013-12-13 Skapad: 2013-12-13 Senast uppdaterad: 2019-10-23Bibliografiskt granskad
Nordlund, J., Bäcklin, C. L., Wahlberg, P., Busche, S., Berglund, E. C., Eloranta, M.-L., . . . Syvänen, A.-C. (2013). Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia. Genome Biology, 14(9), r105
Öppna denna publikation i ny flik eller fönster >>Genome-wide signatures of differential DNA methylation in pediatric acute lymphoblastic leukemia
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2013 (Engelska)Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, nr 9, s. r105-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

BACKGROUND:

Although aberrant DNA methylation has been observed previously in acute lymphoblastic leukemia (ALL), the patterns of differential methylation have not been comprehensively determined in all subtypes of ALL on a genome-wide scale. The relationship between DNA methylation, cytogenetic background, drug resistance and relapse in ALL is poorly understood.

RESULTS:

We surveyed the DNA methylation levels of 435,941 CpG sites in samples from 764 children at diagnosis of ALL and from 27 children at relapse. This survey uncovered four characteristic methylation signatures. First, compared with control blood cells, the methylomes of ALL cells shared 9,406 predominantly hypermethylated CpG sites, independent of cytogenetic background. Second, each cytogenetic subtype of ALL displayed a unique set of hyper- and hypomethylated CpG sites. The CpG sites that constituted these two signatures differed in their functional genomic enrichment to regions with marks of active or repressed chromatin. Third, we identified subtype-specific differential methylation in promoter and enhancer regions that were strongly correlated with gene expression. Fourth, a set of 6,612 CpG sites was predominantly hypermethylated in ALL cells at relapse, compared with matched samples at diagnosis. Analysis of relapse-free survival identified CpG sites with subtype-specific differential methylation that divided the patients into different risk groups, depending on their methylation status.

CONCLUSIONS:

Our results suggest an important biological role for DNA methylation in the differences between ALL subtypes and in their clinical outcome after treatment.

Nationell ämneskategori
Medicinsk genetik
Identifikatorer
urn:nbn:se:uu:diva-208296 (URN)10.1186/gb-2013-14-9-r105 (DOI)000328195700011 ()24063430 (PubMedID)
Anmärkning

De två första författarna delar förstaförfattarskapet.

Tillgänglig från: 2013-09-27 Skapad: 2013-09-27 Senast uppdaterad: 2019-10-23Bibliografiskt granskad
Guy, L., Nystedt, B., Sun, Y., Näslund, K., Berglund, E. C. & Andersson, S. G. E. (2012). A genome-wide study of recombination rate variation in Bartonella henselae. BMC Evolutionary Biology, 12, 65
Öppna denna publikation i ny flik eller fönster >>A genome-wide study of recombination rate variation in Bartonella henselae
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2012 (Engelska)Ingår i: BMC Evolutionary Biology, ISSN 1471-2148, E-ISSN 1471-2148, Vol. 12, s. 65-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Rates of recombination vary by three orders of magnitude in bacteria but the reasons for this variation is unclear. We performed a genome-wide study of recombination rate variation among genes in the intracellular bacterium Bartonella henselae, which has among the lowest estimated ratio of recombination relative to mutation in prokaryotes. Results: The 1.9 Mb genomes of B. henselae strains IC11, UGA10 and Houston-1 genomes showed only minor gene content variation. Nucleotide sequence divergence levels were less than 1% and the relative rate of recombination to mutation was estimated to 1.1 for the genome overall. Four to eight segments per genome presented significantly enhanced divergences, the most pronounced of which were the virB and trw gene clusters for type IV secretion systems that play essential roles in the infection process. Consistently, multiple recombination events were identified inside these gene clusters. High recombination frequencies were also observed for a gene putatively involved in iron metabolism. A phylogenetic study of this gene in 80 strains of Bartonella quintana, B. henselae and B. grahamii indicated different population structures for each species and revealed horizontal gene transfers across Bartonella species with different host preferences. Conclusions: Our analysis has shown little novel gene acquisition in B. henselae, indicative of a closed pan-genome, but higher recombination frequencies within the population than previously estimated. We propose that the dramatically increased fixation rate for recombination events at gene clusters for type IV secretion systems is driven by selection for sequence variability.

Nyckelord
Type IV Secretion Systems, Recombination, Bartonella
Nationell ämneskategori
Naturvetenskap
Identifikatorer
urn:nbn:se:uu:diva-185218 (URN)10.1186/1471-2148-12-65 (DOI)000310328700001 ()
Tillgänglig från: 2012-11-21 Skapad: 2012-11-21 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Nordlund, J., Kiialainen, A., Karlberg, O., Berglund, E. C., Göransson-Kultima, H., Sønderkær, M., . . . Syvänen, A.-C. (2012). Digital gene expression profiling of primary acute lymphoblastic leukemia cells. Leukemia, 26(6), 1218-1227
Öppna denna publikation i ny flik eller fönster >>Digital gene expression profiling of primary acute lymphoblastic leukemia cells
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2012 (Engelska)Ingår i: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 26, nr 6, s. 1218-1227Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

We determined the genome-wide digital gene expression (DGE) profiles of primary acute lymphoblastic leukemia (ALL) cells from 21 patients taking advantage of 'second-generation' sequencing technology. Patients included in this study represent four cytogenetically distinct subtypes of B-cell precursor (BCP) ALL and T-cell lineage ALL (T-ALL). The robustness of DGE combined with supervised classification by nearest shrunken centroids (NSC) was validated experimentally and by comparison with published expression data for large sets of ALL samples. Genes that were differentially expressed between BCP ALL subtypes were enriched to distinct signaling pathways with dic(9;20) enriched to TP53 signaling, t(9;22) to interferon signaling, as well as high hyperdiploidy and t(12;21) to apoptosis signaling. We also observed antisense tags expressed from the non-coding strand of ∼50% of annotated genes, many of which were expressed in a subtype-specific pattern. Antisense tags from 17 gene regions unambiguously discriminated between the BCP ALL and T-ALL subtypes, and antisense tags from 76 gene regions discriminated between the 4 BCP subtypes. We observed a significant overlap of gene regions with alternative polyadenylation and antisense transcription (P<1 × 10(-15)). Our study using DGE profiling provided new insights into the RNA expression patterns in ALL cells.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-168670 (URN)10.1038/leu.2011.358 (DOI)000305081000009 ()22173241 (PubMedID)
Tillgänglig från: 2012-02-14 Skapad: 2012-02-14 Senast uppdaterad: 2019-10-23Bibliografiskt granskad
Berglund, E. C., Kiialainen, A. & Syvänen, A.-C. (2011). Next generation sequencing technologies and applications for human Genetic History and Forensics. Investigative Genetics, 2(1), 23
Öppna denna publikation i ny flik eller fönster >>Next generation sequencing technologies and applications for human Genetic History and Forensics
2011 (Engelska)Ingår i: Investigative Genetics, ISSN 2041-2223, E-ISSN 2041-2223, Vol. 2, nr 1, s. 23-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

The rapid advances in the development of sequencing technologies in recent years enable an increasing number of applications in biology and medicine. Here we review key technical aspects of the preparation of DNA templates for sequencing, the biochemical reaction principles and assay formats underlying next generation sequencing systems, methods for imaging and base calling, quality control, and bioinformatic approaches for sequence alignment, variant calling and assembly. We also discuss some of the most important advances that the new sequencing technologies have brought to the fields of human population genetics, human genetic history and forensic genetics.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-162972 (URN)10.1186/2041-2223-2-23 (DOI)22115430 (PubMedID)
Tillgänglig från: 2011-12-06 Skapad: 2011-12-06 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
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