uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Göransson, Hanna
Alternative names
Publications (10 of 33) Show all publications
Sole, M., Ablondi, M., Binzer, A., Velie, B. D., Hollfelder, N., Buys, N., . . . Lindgren, G. (2019). Inter- and intra-breed genome-wide copy number diversity in a large cohort of European equine breeds. BMC Genomics, 20(1), Article ID 759.
Open this publication in new window or tab >>Inter- and intra-breed genome-wide copy number diversity in a large cohort of European equine breeds
Show others...
2019 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 20, no 1, article id 759Article in journal (Refereed) Published
Abstract [en]

Background Copy Number Variation (CNV) is a common form of genetic variation underlying animal evolution and phenotypic diversity across a wide range of species. In the mammalian genome, high frequency of CNV differentiation between breeds may be candidates for population-specific selection. However, CNV differentiation, selection and its population genetics have been poorly explored in horses. Results We investigated the patterns, population variation and gene annotation of CNV using the Axiom (R) Equine Genotyping Array (670,796 SNPs) from a large cohort of individuals (N = 1755) belonging to eight European horse breeds, varying from draught horses to several warmblood populations. After quality control, 152,640 SNP CNVs (individual markers), 18,800 segment CNVs (consecutive SNP CNVs of same gain/loss state or both) and 939 CNV regions (CNVRs; overlapping segment CNVs by at least 1 bp) compared to the average signal of the reference (Belgian draught horse) were identified. Our analyses showed that Equus caballus chromosome 12 (ECA12) was the most enriched in segment CNV gains and losses (similar to 3% average proportion of the genome covered), but the highest number of segment CNVs were detected on ECA1 and ECA20 (regardless of size). The Friesian horses showed private SNP CNV gains (> 20% of the samples) on ECA1 and Exmoor ponies displayed private SNP CNV losses on ECA25 (> 20% of the samples). The Warmblood cluster showed private SNP CNV gains located in ECA9 and Draught cluster showed private SNP CNV losses located in ECA7. The length of the CNVRs ranged from 1 kb to 21.3 Mb. A total of 10,612 genes were annotated within the CNVRs. The PANTHER annotation of these genes showed significantly under- and overrepresented gene ontology biological terms related to cellular processes and immunity (Bonferroni P-value < 0.05). We identified 80 CNVRs overlapping with known QTL for fertility, coat colour, conformation and temperament. We also report 67 novel CNVRs. Conclusions This work revealed that CNV patterns, in the genome of some European horse breeds, occurred in specific genomic regions. The results provide support to the hypothesis that high frequency private CNVs residing in genes may potentially be responsible for the diverse phenotypes seen between horse breeds.

Place, publisher, year, edition, pages
BMC, 2019
Keywords
Copy number variation, Horse, Structural variation, SNP genotyping array
National Category
Genetics Genetics and Breeding in Agricultural Sciences
Identifiers
urn:nbn:se:uu:diva-397040 (URN)10.1186/s12864-019-6141-z (DOI)000491861300003 ()31640551 (PubMedID)
Funder
Swedish Research Council Formas, 2016-00947
Available from: 2019-11-20 Created: 2019-11-20 Last updated: 2019-11-20Bibliographically approved
Baskaran, S., Mayrhofer, M., Göransson Kultima, H., Bergström, T., Elfineh, L., Cavelier, L., . . . Nelander, S. (2018). Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages. Neuro-Oncology, 20(8), 1080-1091
Open this publication in new window or tab >>Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages
Show others...
2018 (English)In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 8, p. 1080-1091Article in journal (Refereed) Published
Abstract [en]

Background: Primary glioblastoma cell (GC) cultures have emerged as a key model in brain tumor research, with the potential to uncover patient-specific differences in therapy response. However, there is limited quantitative information about the stability of such cells during the initial 20-30 passages of culture.

Methods: We interrogated 3 patient-derived GC cultures at dense time intervals during the first 30 passages of culture. Combining state-of-the-art signal processing methods with a mathematical model of growth, we estimated clonal composition, rates of change, affected pathways, and correlations between altered gene dosage and transcription.

Results: We demonstrate that GC cultures undergo sequential clonal takeovers, observed through variable proportions of specific subchromosomal lesions, variations in aneuploid cell content, and variations in subpopulation cell cycling times. The GC cultures also show significant transcriptional drift in several metabolic and signaling pathways, including ribosomal synthesis, telomere packaging and signaling via the mammalian target of rapamycin, Wnt, and interferon pathways, to a high degree explained by changes in gene dosage. In addition to these adaptations, the cultured GCs showed signs of shifting transcriptional subtype. Compared with chromosomal aberrations and gene expression, DNA methylations remained comparatively stable during passaging, and may be favorable as a biomarker.

Conclusion: Taken together, GC cultures undergo significant genomic and transcriptional changes that need to be considered in functional experiments and biomarker studies that involve primary glioblastoma cells.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS INC, 2018
Keywords
aneuploidy, clones, GBM DNA methylation, GBM subtype, glioma stem cell cultures, patient derived GBM cell cultures, systems biology
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-361042 (URN)10.1093/neuonc/noy024 (DOI)000438338000009 ()29462414 (PubMedID)
Funder
Swedish Research Council, 2014-03314Swedish Cancer Society, CAN 2017/628Swedish Foundation for Strategic Research , BD15-088
Available from: 2018-09-20 Created: 2018-09-20 Last updated: 2018-09-20Bibliographically approved
Bhoi, S., Mansouri, L., Castellano, G., Sutton, L. A., Papakonstantinou, N., Queiros, A., . . . Rosenquist, R. (2017). DNA METHYLATION PROFILING IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS CARRYING STEREOTYPED B-CELL RECEPTORS: A DIFFERENT CELLULAR ORIGIN FOR SUBSET #2?. Paper presented at 22nd Congress of the European-Hematology-Association, JUN 22-25, 2017, Madrid, SPAIN. Haematologica, 102(Suppl. 2), 68-68, Article ID P244.
Open this publication in new window or tab >>DNA METHYLATION PROFILING IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS CARRYING STEREOTYPED B-CELL RECEPTORS: A DIFFERENT CELLULAR ORIGIN FOR SUBSET #2?
Show others...
2017 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 102, no Suppl. 2, p. 68-68, article id P244Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
FERRATA STORTI FOUNDATION, 2017
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-377412 (URN)000404127001140 ()
Conference
22nd Congress of the European-Hematology-Association, JUN 22-25, 2017, Madrid, SPAIN
Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-02-20Bibliographically approved
Kalikstad, B., Göransson Kultima, H., Andersstuen, T. K., Klungland, A. & Isaksson, A. (2017). Gene expression profiles in preterm infants on continuous long-term oxygen therapy suggest reduced oxidative stress-dependent signaling during hypoxia. Molecular Medicine Reports, 15(4), 1513-1526
Open this publication in new window or tab >>Gene expression profiles in preterm infants on continuous long-term oxygen therapy suggest reduced oxidative stress-dependent signaling during hypoxia
Show others...
2017 (English)In: Molecular Medicine Reports, ISSN 1791-2997, E-ISSN 1791-3004, Vol. 15, no 4, p. 1513-1526Article in journal (Refereed) Published
Abstract [en]

Preterm infants are susceptible to neonatal inflammatory/ infective diseases requiring drug therapy. The present study hypothesized that mRNA expression in the blood may be modulated by signaling pathways during treatment. The current study aimed to explore changes in global gene expression in the blood from preterm infants with the objective of identifying patterns or pathways of potential relevance to drug therapy. The infants involved were selected based on maternal criteria indicating increased risk for therapeutic intervention. Global mRNA expression was measured in 107 longitudinal whole blood samples using Affymetrix Human-Genome-U133 Plus 2.0-arrays; samples were obtained from 20 preterm infants. Unsupervised clustering revealed a distinct homogeneous gene expression pattern in 13 samples derived from seven infants undergoing continuous oxygen therapy. At these sampling times, all but one of the seven infants exhibited severe drops in peripheral capillary saturation levels below 60%. The infants were reoxygenated with 100% inspired oxygen concentration. The other samples ( n= 94) represented the infants from the cohort at time points when they did not undergo continuous oxygen therapy. Comparing these two sets of samples identified a distinct gene expression pattern of 5,986 significantly differentially expressed genes, of which 5,167 genes exhibited reduced expression levels during transient hypoxia. This expression pattern was reversed when the infants became stable, i. e., when they were not continuously oxygenated and had no events of hypoxia. To identify signaling pathways involved in gene regulation, the Database for Annotation, Visualization and Integrated Discovery online tool was used. Mitogen-activated protein kinases, which are normally induced by oxidative stress, exhibited reduced gene expression during hypoxia. In addition, nuclear factor erythroid 2-related factor 2-antioxidant response element target genes involved in oxidative stress protection were also expressed at lower levels, suggesting reduced transcription of this pathway. The findings of the present study suggest that oxidative stress-dependent signaling is reduced during hypoxia. Understanding the molecular response in preterm infants during continuous oxygenation may aid in refining therapeutic strategies for oxygen therapy.

Keywords
gene expression profile, preterm infants, transcription, molecular pattern, signaling pathway
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Cell and Molecular Biology Pediatrics
Identifiers
urn:nbn:se:uu:diva-322848 (URN)10.3892/mmr.2017.6185 (DOI)000397203200010 ()28259955 (PubMedID)
Available from: 2017-06-07 Created: 2017-06-07 Last updated: 2018-01-13Bibliographically approved
Hakelius, M., Saiepour, D., Göransson, H. K., Rubin, K., Gerdin, B. & Nowinski, D. (2015). Differential Gene Regulation in Fibroblasts in Co-culture with Keratinocytes and Head and Neck SCC Cells. Anticancer Research, 35(6), 3253-3265
Open this publication in new window or tab >>Differential Gene Regulation in Fibroblasts in Co-culture with Keratinocytes and Head and Neck SCC Cells
Show others...
2015 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 35, no 6, p. 3253-3265Article in journal (Refereed) Published
Abstract [en]

Background: While carcinoma-associated fibroblasts (CAFs) support tumorigenesis, normal tissue fibroblasts suppress tumor progression. Mechanisms behind conversion of fibroblasts into a CAF phenotype are largely unrevealed. Materials and Methods: Transwell co-cultures with fibroblasts in collagen gels and squamous-cell carcinoma (SCC) cells or normal oral keratinocytes (NOKs) in inserts. Differences in fibroblast global gene expression were analyzed using Affymetrix arrays and subsequent functional annotation and cluster analysis, as well as gene set enrichment analysis were performed. Results: There were 52 up-regulated and 30 down-regulated transcript IDs (>2-fold, p<0.05) in fibroblasts co-cultured with SCC compared to NOKs. Functional analysis demonstrated an enrichment of collagen-related genes. There were similarities with gene sets reflecting a non-specific, innate-type response with activation of both interferon pathways and connective tissue turnover. Conclusion: There were distinct differences in fibroblast gene expression between the co-culture types. Many were in genes related to an innate-type of response and to connective tissue turnover.

Keywords
Head and neck cancer, keratinocytes, differential gene regulation, array
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-256809 (URN)000355273800015 ()26026085 (PubMedID)
Available from: 2015-06-29 Created: 2015-06-26 Last updated: 2017-12-04Bibliographically approved
Mengelbier, L. H., Karlsson, J., Lindgren, D., Valind, A., Lilljebjorn, H., Jansson, C., . . . Gisselsson, D. (2015). Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer. Nature Communications, 6, Article ID 6125.
Open this publication in new window or tab >>Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer
Show others...
2015 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, article id 6125Article in journal (Refereed) Published
Abstract [en]

Genetic differences among neoplastic cells within the same tumour have been proposed to drive cancer progression and treatment failure. Whether data on intratumoral diversity can be used to predict clinical outcome remains unclear. We here address this issue by quantifying genetic intratumoral diversity in a set of chemotherapy-treated childhood tumours. By analysis of multiple tumour samples from seven patients we demonstrate intratumoral diversity in all patients analysed after chemotherapy, typically presenting as multiple clones within a single millimetre-sized tumour sample (microdiversity). We show that microdiversity often acts as the foundation for further genome evolution in metastases. In addition, we find that microdiversity predicts poor cancer-specific survival (60%; P = 0.009), independent of other risk factors, in a cohort of 44 patients with chemotherapy-treated childhood kidney cancer. Survival was 100% for patients lacking microdiversity. Thus, intratumoral genetic diversity is common in childhood cancers after chemotherapy and may be an important factor behind treatment failure.

National Category
Medical Genetics Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-246672 (URN)10.1038/ncomms7125 (DOI)000348832000001 ()25625758 (PubMedID)
Available from: 2015-03-18 Created: 2015-03-09 Last updated: 2018-01-11Bibliographically approved
Birgisson, H., Edlund, K., Wallin, U., Påhlman, L., Kultima, H. G., Mayrhofer, M., . . . Sundström, M. (2015). Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer. BMC Cancer, 15, Article ID 125.
Open this publication in new window or tab >>Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer
Show others...
2015 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, article id 125Article in journal (Refereed) Published
Abstract [en]

Background: Molecular alterations are well studied in colon cancer, however there is still need for an improved understanding of their prognostic impact. This study aims to characterize colon cancer with regard to KRAS, BRAF, and PIK3CA mutations, microsatellite instability (MSI), and average DNA copy number, in connection with tumour dissemination and recurrence in patients with colon cancer. Methods: Disease stage II-IV colon cancer patients (n = 121) were selected. KRAS, BRAF, and PIK3CA mutation status was assessed by pyrosequencing and MSI was determined by analysis of mononucleotide repeat markers. Genome-wide average DNA copy number and allelic imbalance was evaluated by SNP array analysis. Results: Patients with mutated KRAS were more likely to experience disease dissemination (OR 2.75; 95% CI 1.28-6.04), whereas the opposite was observed for patients with BRAF mutation (OR 0.34; 95% 0.14-0.81) or MSI (OR 0.24; 95% 0.09-0.64). Also in the subset of patients with stage II-III disease, both MSI (OR 0.29; 95% 0.10-0.86) and BRAF mutation (OR 0.32; 95% 0.16-0.91) were related to lower risk of distant recurrence. However, average DNA copy number and PIK3CA mutations were not associated with disease dissemination. Conclusions: The present study revealed that tumour dissemination is less likely to occur in colon cancer patients with MSI and BRAF mutation, whereas the presence of a KRAS mutation increases the likelihood of disseminated disease.

Keywords
Colon cancer, MSI, BRAF, KRAS, PIK3CA, DNA copy number, Prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-251424 (URN)10.1186/s12885-015-1144-x (DOI)000351047900001 ()
Available from: 2015-04-23 Created: 2015-04-17 Last updated: 2018-02-01Bibliographically approved
Mayrhofer, M., Kultima, H. G., Birgisson, H., Sundström, M., Mathot, L., Edlund, K., . . . Isaksson, A. (2014). 1p36 deletion is a marker for tumour dissemination in microsatellite stable stage II-III colon cancer. BMC Cancer, 14, 872
Open this publication in new window or tab >>1p36 deletion is a marker for tumour dissemination in microsatellite stable stage II-III colon cancer
Show others...
2014 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 14, p. 872-Article in journal (Refereed) Published
Abstract [en]

Background: The clinical behaviour of colon cancer is heterogeneous. Five-year overall survival is 50-65% with all stages included. Recurring somatic chromosomal alterations have been identified and some have shown potential as markers for dissemination of the tumour, which is responsible for most colon cancer deaths. We investigated 115 selected stage II-IV primary colon cancers for associations between chromosomal alterations and tumour dissemination. Methods: Follow-up was at least 5 years for stage II-III patients without distant recurrence. Affymetrix SNP 6.0 microarrays and allele-specific copy number analysis were used to identify chromosomal alterations. Fisher's exact test was used to associate alterations with tumour dissemination, detected at diagnosis (stage IV) or later as recurrent disease (stage II-III). Results: Loss of 1p36.11-21 was associated with tumour dissemination in microsatellite stable tumours of stage II-IV (odds ratio = 5.5). It was enriched to a similar extent in tumours with distant recurrence within stage II and stage III subgroups, and may therefore be used as a prognostic marker at diagnosis. Loss of 1p36.11-21 relative to average copy number of the genome showed similar prognostic value compared to absolute loss of copies. Therefore, the use of relative loss as a prognostic marker would benefit more patients by applying also to hyperploid cancer genomes. The association with tumour dissemination was supported by independent data from the The Cancer Genome Atlas. Conclusion: Deletions on 1p36 may be used to guide adjuvant treatment decisions in microsatellite stable colon cancer of stages II and III.

Keywords
Colon cancer, Prognostic marker, Allele-specific copy number analysis, Genome duplication, 1p36, Metastasis, Tumour dissemination
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-240088 (URN)10.1186/1471-2407-14-872 (DOI)000345660000001 ()25420937 (PubMedID)
Available from: 2015-01-05 Created: 2015-01-05 Last updated: 2018-02-01Bibliographically approved
Eriksson, A., Kalushkova, A., Jarvius, M., Hilhorst, R., Rickardson, L., Göransson Kultima, H., . . . Höglund, M. (2014). AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and a dose dependent reduction of kinase activity in acute myeloid leukemia. Biochemical Pharmacology, 87(2), 284-291
Open this publication in new window or tab >>AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and a dose dependent reduction of kinase activity in acute myeloid leukemia
Show others...
2014 (English)In: Biochemical Pharmacology, ISSN 0006-2952, E-ISSN 1356-1839, Vol. 87, no 2, p. 284-291Article in journal (Refereed) Published
Abstract [en]

AKN-028 is a novel tyrosine kinase inhibitor with preclinical activity in acute myeloid leukemia (AML), presently undergoing investigation in a phase I/II study. It is a potent inhibitor of the FMS-like kinase 3 (FLT3) but shows in vitro activity in a wide range of AML samples. In the present study, we have characterized the effects of AKN-028 on AML cells in more detail. AKN-028 induced a dose-dependent G(0)/arrest in AML cell line MV4-11. Treatment with AKN-028 caused significantly altered gene expression in all AML cell types tested (430 downregulated, 280 upregulated transcripts). Subsequent gene set enrichment analysis revealed enrichment of genes associated with the proto-oncogene and cell cycle regulator c-Myc among the downregulated genes in both AKN-028 and midostaurin treated cells. Kinase activity profiling in AML cell lines and primary AML samples showed that tyrosine kinase activity, but not serine/threonine kinase activity, was inhibited by AKN-028 in a dose dependent manner in all samples tested, reaching approximately the same level of kinase activity. Cells sensitive to AKN-028 showed a higher overall tyrosine kinase activity than more resistant ones, whereas serine/threonine kinase activity was similar for all primary AML samples. In summary, AKN-028 induces cell cycle arrest in AML cells, downregulates Myc-associated genes and affect several signaling pathways. AML cells with high global tyrosine kinase activity seem to be more sensitive to the cytotoxic effect of AKN-028 in vitro.

Place, publisher, year, edition, pages
Elsevier, 2014
Keywords
Acute myeloid leukemia, AKN-028, Tyrosine kinase inhibitor, Signal transduction
National Category
Hematology Pharmacology and Toxicology Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-182065 (URN)10.1016/j.bcp.2013.10.022 (DOI)000330332800006 ()
Available from: 2012-10-10 Created: 2012-10-03 Last updated: 2018-01-12Bibliographically approved
Cahill, N., Bergh, A.-C., Kanduri, M., Göransson-Kultima, H., Mansouri, L., Isaksson, A., . . . Rosenquist, R. (2013). 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments.. Leukemia, 27(1), 150-158
Open this publication in new window or tab >>450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments.
Show others...
2013 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 27, no 1, p. 150-158Article in journal (Refereed) Published
Abstract [en]

In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-β and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.

National Category
Clinical Laboratory Medicine Basic Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-189871 (URN)10.1038/leu.2012.245 (DOI)000313511400021 ()22922567 (PubMedID)
Available from: 2013-01-04 Created: 2013-01-04 Last updated: 2018-01-11
Organisations

Search in DiVA

Show all publications