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Binzer-Panchal, A., Hardell, E., Viklund, B., Ghaderi, M., Bosse, T., Nucci, M. R., . . . Carlson, J. W. (2019). Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes. Clinical Cancer Research, 25(7), 2155-2165
Open this publication in new window or tab >>Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes
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2019 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 25, no 7, p. 2155-2165Article in journal (Refereed) Published
Abstract [en]

Purpose: Undifferentiated uterine sarcomas (UUS) are rare, extremely deadly, sarcomas with no effective treatment. The goal of this study was to identify novel intrinsic molecular UUS subtypes using integrated clinical, histopathologic, and molecular evaluation of a large, fully annotated, patient cohort.

Experimental Design: Fifty cases of UUS with full clinicopathologic annotation were analyzed for gene expression (n = 50), copy-number variation (CNV, n = 40), cell morphometry (n = 39), and protein expression (n = 22). Gene ontology and network enrichment analysis were used to relate over-and underexpressed genes to pathways and further to clinicopathologic and phenotypic findings.

Results: Gene expression identified four distinct groups of tumors, which varied in their clinicopathologic parameters. Gene ontology analysis revealed differential activation of pathways related to genital tract development, extracellular matrix (ECM), muscle function, and proliferation. A multivariable, adjusted Cox proportional hazard model demonstrated that RNA group, mitotic index, and hormone receptor expression influence patient overall survival (OS). CNV arrays revealed characteristic chromosomal changes for each group. Morphometry demonstrated that the ECM group, the most aggressive, exhibited a decreased cell density and increased nuclear area. A cell density cutoff of 4,300 tumor cells per mm(2) could separate ECM tumors from the remaining cases with a sensitivity of 83% and a specificity of 94%. IHC staining of MMP-14, Collagens 1 and 6, and Fibronectin proteins revealed differential expression of these ECM-related proteins, identifying potential new biomarkers for this aggressive sarcoma subgroup. Conclusions: Molecular evaluation of UUS provides novel insights into the biology, prognosis, phenotype, and possible treatment of these tumors.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH, 2019
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-382512 (URN)10.1158/1078-0432.CCR-18-2792 (DOI)000462991900019 ()30617134 (PubMedID)
Funder
The Cancer Research Funds of RadiumhemmetSwedish Cancer SocietyMagnus Bergvall FoundationStockholm County Council
Available from: 2019-04-30 Created: 2019-04-30 Last updated: 2019-04-30Bibliographically approved
Hofvander, J., Viklund, B., Isaksson, A., Brosjo, O., von Steyern, F. V., Rissler, P., . . . Mertens, F. (2018). Different patterns of clonal evolution among different sarcoma subtypes followed for up to 25 years. Nature Communications, 9, Article ID 3662.
Open this publication in new window or tab >>Different patterns of clonal evolution among different sarcoma subtypes followed for up to 25 years
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2018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 3662Article in journal (Refereed) Published
Abstract [en]

To compare clonal evolution in tumors arising through different mechanisms, we selected three types of sarcoma-amplicon-driven well-differentiated liposarcoma (WDLS), gene fusion-driven myxoid liposarcoma (MLS), and sarcomas with complex genomes (CXS)-and assessed the dynamics of chromosome and nucleotide level mutations by cytogenetics, SNP array analysis and whole-exome sequencing. Here we show that the extensive single-cell variation in WDLS has minor impact on clonal key amplicons in chromosome 12. In addition, only a few of the single nucleotide variants in WDLS were present in more than one lesion, suggesting that such mutations are of little significance in tumor development. MLS displays few mutations other than the FUS-DDIT3 fusion, and the primary tumor is genetically sometimes much more complex than its relapses, whereas CXS in general shows a gradual increase of both nucleotide- and chromosome-level mutations, similar to what has been described in carcinomas.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-365649 (URN)10.1038/s41467-018-06098-0 (DOI)000444078300005 ()30201954 (PubMedID)
Funder
Swedish Cancer Society, CAN2017/269
Available from: 2018-11-14 Created: 2018-11-14 Last updated: 2018-11-14Bibliographically approved
Karlsson, J., Valind, A., Mengelbier, L. H., Bredin, S., Cornmark, L., Jansson, C., . . . Gisselsson, D. (2018). Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer. Nature Genetics, 50(7), 944-950
Open this publication in new window or tab >>Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer
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2018 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 50, no 7, p. 944-950Article in journal (Refereed) Published
Abstract [en]

A major challenge to personalized oncology is that driver mutations vary among cancer cells inhabiting the same tumor. Whether this reflects principally disparate patterns of Darwinian evolution in different tumor regions has remained unexplored(1-5). We mapped the prevalence of genetically distinct clones over 250 regions in 54 childhood cancers. This showed that primary tumors can simultaneously follow up to four evolutionary trajectories over different anatomic areas. The most common pattern consists of subclones with very few mutations confined to a single tumor region. The second most common is a stable coexistence, over vast areas, of clones characterized by changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a clone with driver mutations or structural chromosome rearrangements emerges through a clonal sweep to dominate an anatomical region. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53 inactivation. Death from disease was limited to tumors exhibiting the two last, most dynamic patterns.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-361111 (URN)10.1038/s41588-018-0131-y (DOI)000437224400009 ()29867221 (PubMedID)
Funder
Swedish Research Council, 2016-01022Swedish Cancer Society, CAN2015/284Swedish Childhood Cancer Foundation, PR2016-024Swedish Childhood Cancer Foundation, NCP2015-0035
Available from: 2018-09-21 Created: 2018-09-21 Last updated: 2018-09-21Bibliographically approved
Danesi, C., Achuta, V. S., Corcoran, P., Peteri, U.-K., Turconi, G., Matsui, N., . . . Castren, M. L. (2018). Increased Calcium Influx through L-type Calcium Channels in Human and Mouse Neural Progenitors Lacking Fragile X Mental Retardation Protein. Stem Cell Reports, 11(6), 1449-1461
Open this publication in new window or tab >>Increased Calcium Influx through L-type Calcium Channels in Human and Mouse Neural Progenitors Lacking Fragile X Mental Retardation Protein
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2018 (English)In: Stem Cell Reports, ISSN 2213-6711, Vol. 11, no 6, p. 1449-1461Article in journal (Refereed) Published
Abstract [en]

The absence of FMR1 protein (FMRP) causes fragile X syndrome (FXS) and disturbed FMRP function is implicated in several forms of human psychopathology. We show that intracellular calcium responses to depolarization are augmented in neural progenitors derived from human induced pluripotent stem cells and mouse brain with FXS. Increased calcium influx via nifedipine-sensitive voltage-gated calcium (Ca-v) channels contributes to the exaggerated responses to depolarization and type 1 metabotropic glutamate receptor activation. The ratio of L-type/T-type Ca-v channel expression is increased in FXS progenitors and correlates with enhanced progenitor differentiation to glutamate-responsive cells. Genetic reduction of brain-derived neurotrophic factor in FXS mouse progenitors diminishes the expression of Ca-v channels and activity-dependent responses, which are associated with increased phosphorylation of the phospholipase C-gamma 1 site within TrkB receptors and changes of differentiating progenitor subpopulations. Our results show developmental effects of increased calcium influx via L-type Ca-v channels in FXS neural progenitors.

National Category
Cell and Molecular Biology Neurosciences
Identifiers
urn:nbn:se:uu:diva-372938 (URN)10.1016/j.stemcr.2018.11.003 (DOI)000452898300016 ()30503263 (PubMedID)
Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-01-10Bibliographically approved
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
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
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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?
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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
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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
Mandahl, N., Magnusson, L., Nilsson, J., Viklund, B., Arbajian, E., von Steyern, F. V., . . . Mertens, F. (2017). Scattered genomic amplification in dedifferentiated liposarcoma. Molecular Cytogenetics, 10, Article ID 25.
Open this publication in new window or tab >>Scattered genomic amplification in dedifferentiated liposarcoma
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2017 (English)In: Molecular Cytogenetics, ISSN 1755-8166, E-ISSN 1755-8166, Vol. 10, article id 25Article in journal (Refereed) Published
Abstract [en]

Background: Atypical lipomatous tumor (ALT), well differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS) are cytogenetically characterized by near-diploid karyotypes with no or few other aberrations than supernumerary ring or giant marker chromosomes, although DDLS tend to have somewhat more complex rearrangements. In contrast, pleomorphic liposarcomas (PLS) have highly aberrant and heterogeneous karyotypes. The ring and giant marker chromosomes contain discontinuous amplicons, in particular including multiple copies of the target genes CDK4, HMGA2 and MDM2 from 12q, but often also sequences from other chromosomes.

Results: The present study presents a DDLS with an atypical hypertriploid karyotype without any ring or giant marker chromosomes. SNP array analyses revealed amplification of almost the entire 5p and discontinuous amplicons of 12q including the classical target genes, in particular CDK4. In addition, amplicons from 1q, 3q, 7p, 9p, 11q and 20q, covering from 2 to 14 Mb, were present. FISH analyses showed that sequences from 5p and 12q were scattered, separately or together, over more than 10 chromosomes of varying size. At RNA sequencing, significantly elevated expression, compared to myxoid liposarcomas, was seen for TRIO and AMACR in 5p and of CDK4, HMGA2 and MDM2 in 12q.

Conclusions: The observed pattern of scattered amplification does not show the characteristics of chromothripsis, but is novel and differs from the well known cytogenetic manifestations of amplification, i. e., double minutes, homogeneously staining regions and ring chromosomes. Possible explanations for this unusual distribution of amplified sequences might be the mechanism of alternative lengthening of telomeres that is frequently active in DDLS and events associated with telomere crisis.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD, 2017
Keywords
Liposarcoma, Chromosomes, Amplification, 5p, 12q, Gene expression
National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-329641 (URN)10.1186/s13039-017-0325-5 (DOI)000404100100001 ()28652867 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2017-09-21 Created: 2017-09-21 Last updated: 2018-01-13Bibliographically approved
Mayrhofer, M., Viklund, B. & Isaksson, A. (2016). Rawcopy: Improved copy number analysis with Affymetrix arrays. Scientific Reports, 6, Article ID 36158.
Open this publication in new window or tab >>Rawcopy: Improved copy number analysis with Affymetrix arrays
2016 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 36158Article in journal (Refereed) Published
Abstract [en]

Microarray data is subject to noise and systematic variation that negatively affects the resolution of copy number analysis. We describe Rawcopy, an R package for processing of Affymetrix CytoScan HD, CytoScan 750k and SNP 6.0 microarray raw intensities (CEL files). Noise characteristics of a large number of reference samples are used to estimate log ratio and B-allele frequency for total and allele-specific copy number analysis. Rawcopy achieves better signal-to-noise ratio and higher proportion of validated alterations than commonly used free and proprietary alternatives. In addition, Rawcopy visualizes each microarray sample for assessment of technical quality, patient identity and genome-wide absolute copy number states. Software and instructions are available at http://rawcopy.org.

National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:uu:diva-308636 (URN)10.1038/srep36158 (DOI)000386461800001 ()27796336 (PubMedID)
Funder
Swedish Cancer Society
Available from: 2016-11-30 Created: 2016-11-29 Last updated: 2017-11-29Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6576-7825

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