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Publications (10 of 18) Show all publications
de Ståhl, T. D., Shamikh, A., Mayrhofer, M., Juhos, S., Basmaci, E., Prochazka, G., . . . Nistér, M. (2023). The Swedish childhood tumor biobank: systematic collection and molecular characterization of all pediatric CNS and other solid tumors in Sweden. Journal of Translational Medicine, 21, Article ID 342.
Open this publication in new window or tab >>The Swedish childhood tumor biobank: systematic collection and molecular characterization of all pediatric CNS and other solid tumors in Sweden
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2023 (English)In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 21, article id 342Article in journal (Refereed) Published
Abstract [en]

The Swedish Childhood Tumor Biobank (BTB) is a nonprofit national infrastructure for collecting tissue samples and genomic data from pediatric patients diagnosed with central nervous system (CNS) and other solid tumors. The BTB is built on a multidisciplinary network established to provide the scientific community with standardized biospecimens and genomic data, thereby improving knowledge of the biology, treatment and outcome of childhood tumors. As of 2022, over 1100 fresh-frozen tumor samples are available for researchers. We present the workflow of the BTB from sample collection and processing to the generation of genomic data and services offered. To determine the research and clinical utility of the data, we performed bioinformatics analyses on next-generation sequencing (NGS) data obtained from a subset of 82 brain tumors and patient blood-derived DNA combined with methylation profiling to enhance the diagnostic accuracy and identified germline and somatic alterations with potential biological or clinical significance. The BTB procedures for collection, processing, sequencing, and bioinformatics deliver high-quality data. We observed that the findings could impact patient management by confirming or clarifying the diagnosis in 79 of the 82 tumors and detecting known or likely driver mutations in 68 of 79 patients. In addition to revealing known mutations in a broad spectrum of genes implicated in pediatric cancer, we discovered numerous alterations that may represent novel driver events and specific tumor entities. In summary, these examples reveal the power of NGS to identify a wide number of actionable gene alterations. Making the power of NGS available in healthcare is a challenging task requiring the integration of the work of clinical specialists and cancer biologists; this approach requires a dedicated infrastructure, as exemplified here by the BTB.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2023
Keywords
Biobank, Genomic, Childhood cancer, Next generation sequence, Mutation, Bioinformatics, Methylation
National Category
Cancer and Oncology Cell and Molecular Biology Bioinformatics and Systems Biology
Identifiers
urn:nbn:se:uu:diva-506579 (URN)10.1186/s12967-023-04178-4 (DOI)000993861500002 ()37221626 (PubMedID)
Funder
Knut and Alice Wallenberg FoundationSwedish Research CouncilSwedish National Infrastructure for Computing (SNIC)
Available from: 2023-06-28 Created: 2023-06-28 Last updated: 2023-06-28Bibliographically approved
Stratmann, S., Yones, S. A., Garbulowski, M., Sun, J., Skaftason, A., Mayrhofer, M., . . . Holmfeldt, L. (2022). Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression. Blood Advances, 6(1), 152-164
Open this publication in new window or tab >>Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression
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2022 (English)In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 6, no 1, p. 152-164Article in journal (Refereed) Published
Abstract [en]

Numerous studies have been performed over the last decade to exploit the complexity of genomic and transcriptomic lesions driving the initiation of acute myeloid leukemia (AML). These studies have helped improve risk classification and treatment options. Detailed molecular characterization of longitudinal AML samples is sparse, however; meanwhile, relapse and therapy resistance represent the main challenges in AML care. To this end, we performed transcriptome-wide RNA sequencing of longitudinal diagnosis, relapse, and/or primary resistant samples from 47 adult and 23 pediatric AML patients with known mutational background. Gene expression analysis revealed the association of short event-free survival with overexpression of GLI2 and IL1R1, as well as downregulation of ST18. Moreover, CR1 downregulation and DPEP1 upregulation were associated with AML relapse both in adults and children. Finally, machine learning–based and network-based analysis identified overexpressed CD6 and downregulated INSR as highly copredictive genes depicting important relapse-associated characteristics among adult patients with AML. Our findings highlight the importance of a tumor-promoting inflammatory environment in leukemia progression, as indicated by several of the herein identified differentially expressed genes. Together, this knowledge provides the foundation for novel personalized drug targets and has the potential to maximize the benefit of current treatments to improve cure rates in AML.

Place, publisher, year, edition, pages
American Society of HematologyAmerican Society of Hematology (ASH), 2022
Keywords
Acute myeloid leukemia, RNA-sequencing, relapse and resistance, machine learning-based analysis
National Category
Cancer and Oncology Hematology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-427202 (URN)10.1182/bloodadvances.2021004962 (DOI)000753720500016 ()34619772 (PubMedID)
Funder
Swedish Research Council, 2018-05973Knut and Alice Wallenberg Foundation, 2013-0159Swedish National Infrastructure for Computing (SNIC), sens2017604Swedish National Infrastructure for Computing (SNIC), sens2018512Swedish Research Council, 2013-03486Swedish Childhood Cancer Foundation, PR2013-0070Swedish Childhood Cancer Foundation, TJ2013-0045Swedish Cancer Society, CAN2013/489Kjell and Marta Beijer FoundationeSSENCE - An eScience CollaborationNIH (National Institute of Health), HHSN272201700010I
Note

De två första författarna delar förstaförfattarskapet

Available from: 2020-12-03 Created: 2020-12-03 Last updated: 2024-01-15Bibliographically approved
Stratmann, S., Yones, S. A., Mayrhofer, M., Norgren, N., Skaftason, A., Sun, J., . . . Holmfeldt, L. (2021). Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets. Blood Advances, 5(3), 900-912
Open this publication in new window or tab >>Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets
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2021 (English)In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 5, no 3, p. 900-912Article in journal (Refereed) Published
Abstract [en]

Relapse is the leading cause of death of adult and pediatric patients with acute myeloid leukemia (AML). Numerous studies have helped to elucidate the complex mutational landscape at diagnosis of AML, leading to improved risk stratification and new therapeutic options. However, multi–whole-genome studies of adult and pediatric AML at relapse are necessary for further advances. To this end, we performed whole-genome and whole-exome sequencing analyses of longitudinal diagnosis, relapse, and/or primary resistant specimens from 48 adult and 25 pediatric patients with AML. We identified mutations recurrently gained at relapse in ARID1A and CSF1R, both of which represent potentially actionable therapeutic alternatives. Further, we report specific differences in the mutational spectrum between adult vs pediatric relapsed AML, with MGA and H3F3A p.Lys28Met mutations recurrently found at relapse in adults, whereas internal tandem duplications in UBTF were identified solely in children. Finally, our study revealed recurrent mutations in IKZF1, KANSL1, and NIPBL at relapse. All of the mentioned genes have either never been reported at diagnosis in de novo AML or have been reported at low frequency, suggesting important roles for these alterations predominantly in disease progression and/or resistance to therapy. Our findings shed further light on the complexity of relapsed AML and identified previously unappreciated alterations that may lead to improved outcomes through personalized medicine.

Place, publisher, year, edition, pages
American Society of Hematology, 2021
Keywords
acute myeloid leukemia, whole genome sequencing, relapse and resistance
National Category
Cancer and Oncology Hematology
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-427147 (URN)10.1182/bloodadvances.2020003709 (DOI)000617538500026 ()33560403 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation, KAW 2013-0159Swedish Research Council, 2013-03486Swedish Research Council, 2018-05973Swedish Research Council, SNIC sens2017148Swedish Research Council, SNIC sens2018102European Commission, PR2013-0070European Commission, TJ2013-0045Swedish Cancer Society, CAN2013/489Kjell and Marta Beijer FoundationeSSENCE - An eScience Collaboration
Note

Manuscript title: Genomic characterization of adult and pediatric relapsed acute myeloid leukemia reveals novel therapeutic targets: Genomic studies of relapsed acute myeloid leukemia

Available from: 2020-12-03 Created: 2020-12-03 Last updated: 2024-01-15Bibliographically approved
Stratmann, S., Yones, S. A., Garbulowski, M., Sun, J., Skaftason, A., Mayrhofer, M., . . . Holmfeldt, L. (2021). SUPPLEMENTARY MATERIAL: Transcriptomic analysis reveals pro-inflammatory signatures associated with acute myeloid leukemia progression.
Open this publication in new window or tab >>SUPPLEMENTARY MATERIAL: Transcriptomic analysis reveals pro-inflammatory signatures associated with acute myeloid leukemia progression
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2021 (English)Data set
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:uu:diva-455314 (URN)
Available from: 2021-10-05 Created: 2021-10-05 Last updated: 2022-09-14Bibliographically approved
Stratmann, S., Yones, S. A., Garbulowski, M., Sun, J., Skaftason, A., Mayrhofer, M., . . . Holmfeldt, L. (2020). SUPPLEMENTAL INFORMATION FOR: Transcriptomic analysis reveals pro-inflammatory signatures associated with acute myeloid leukemia progression.
Open this publication in new window or tab >>SUPPLEMENTAL INFORMATION FOR: Transcriptomic analysis reveals pro-inflammatory signatures associated with acute myeloid leukemia progression
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2020 (English)Data set
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-427506 (URN)
Available from: 2020-12-10 Created: 2020-12-10 Last updated: 2022-09-14Bibliographically 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: 2020-11-04Bibliographically approved
Mathot, L., Kundu, S., Ljungström, V., Svedlund, J., Moens, L., Adlerteg, T., . . . Sjöblom, T. (2017). Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer. Cancer Research, 77(7), 1730-1740
Open this publication in new window or tab >>Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer
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2017 (English)In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 7, p. 1730-1740Article in journal (Refereed) Published
Abstract [en]

The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1-induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer.

National Category
Clinical Laboratory Medicine Cancer and Oncology
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-319146 (URN)10.1158/0008-5472.CAN-16-1921 (DOI)000398262400019 ()28108514 (PubMedID)
Funder
Swedish Cancer Society, 2006/2154EU, European Research Council, 601939Swedish Foundation for Strategic Research , F06-0050VinnovaSwedish Cancer Society, 2012/834Swedish Cancer Society, 2007/775
Available from: 2017-03-31 Created: 2017-03-31 Last updated: 2020-04-17Bibliographically approved
Walther, C., Mayrhofer, M., Nilsson, J., Hofvander, J., Jonson, T., Mandahl, N., . . . Mertens, F. (2016). Genetic Heterogeneity in Rhabdomyosarcoma Revealed by SNP Array Analysis. Genes, Chromosomes and Cancer, 55(1), 3-15
Open this publication in new window or tab >>Genetic Heterogeneity in Rhabdomyosarcoma Revealed by SNP Array Analysis
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2016 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 55, no 1, p. 3-15Article in journal (Refereed) Published
Abstract [en]

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents. Alveolar (ARMS) and embryonal (ERMS) histologies predominate, but rare cases are classified as spindle cell/sclerosing (SRMS). For treatment stratification, RMS is further subclassified as fusion-positive (FP-RMS) or fusion-negative (FN-RMS), depending on whether a gene fusion involving PAX3 or PAX7 is present or not. We investigated 19 cases of pediatric RMS using high resolution single-nucleotide polymorphism (SNP) array. FP-ARMS displayed, on average, more structural rearrangements than ERMS; the single FN-ARMS had a genomic profile similar to ERMS. Apart from previously known amplification (e.g., MYCN, CDK4, and MIR17HG) and deletion (e.g., NF1, CDKN2A, and CDKN2B) targets, amplification of ERBB2 and homozygous loss of ASCC3 or ODZ3 were seen. Combining SNP array with cytogenetic data revealed that most cases were polyploid, with at least one case having started as a near-haploid tumor. Further bioinformatic analysis of the SNP array data disclosed genetic heterogeneity, in the form of subclonal chromosomal imbalances, in five tumors. The outcome was worse for patients with FP-ARMS than ERMS or FN-ARMS (6/8 vs. 1/9 dead of disease), and the only children with ERMS showing intratumor diversity or with MYOD1 mutation-positive SRMS also died of disease. High resolution SNP array can be useful in evaluating genomic imbalances in pediatric RMS.

National Category
Cancer and Oncology Medical Genetics
Identifiers
urn:nbn:se:uu:diva-276867 (URN)10.1002/gcc.22285 (DOI)000368259400001 ()26482321 (PubMedID)
Funder
Swedish Childhood Cancer Foundation
Available from: 2016-02-16 Created: 2016-02-16 Last updated: 2018-01-10Bibliographically 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, 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: 2022-09-15Bibliographically approved
Mayrhofer, M. (2015). Copy Number Analysis of Cancer. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>Copy Number Analysis of Cancer
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

By accurately describing cancer genomes, we may link genomic mutations to phenotypic effects and eventually treat cancer patients based on the molecular cause of their disease, rather than generalizing treatment based on cell morphology or tissue of origin.

Alteration of DNA copy number is a driving mutational process in the formation and progression of cancer. Deletions and amplifications of specific chromosomal regions are important for cancer diagnosis and prognosis, and copy number analysis has become standard practice for many clinicians and researchers. In this thesis we describe the development of two computational methods, TAPS and Patchwork, for analysis of genome-wide absolute allele-specific copy number per cell in tumour samples. TAPS is used with SNP microarray data and Patchwork with whole genome sequencing data. Both are suitable for unknown average ploidy of the tumour cells, are robust to admixture of genetically normal cells, and may be used to detect genetic heterogeneity in the tumour cell population. We also present two studies where TAPS was used to find copy number alterations associated with risk of recurrence after surgery, in ovarian cancer and colon cancer. We discuss the potential of such prognostic markers and the use of allele-specific copy number analysis in research and diagnostics.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. p. 42
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1072
Keywords
chromosomes, oncology, bioinformatics
National Category
Bioinformatics (Computational Biology) Genetics Cancer and Oncology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Bioinformatics; Oncology; Clinical Genetics
Identifiers
urn:nbn:se:uu:diva-244361 (URN)978-91-554-9175-8 (ISBN)
Public defence
2015-04-17, BMC E10:1307-1309, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2015-03-26 Created: 2015-02-16 Last updated: 2018-01-11
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0003-3403-0083

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