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  • 1.
    Baskaran, Sathishkumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Göransson Kultima, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Isaksson, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 8, p. 1080-1091Article in journal (Refereed)
    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.

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  • 2.
    Birgisson, Helgi
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Edlund, Karolina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Wallin, Ulrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Påhlman, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Kultima, Hanna Göransson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer2015In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, article id 125Article in journal (Refereed)
    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.

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  • 3.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Backman, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Maharjan, Rajani
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Björklund, Peyman
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis.2015In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 19, p. 4451-4460Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Pheochromocytoma and paraganglioma (PPGL) patients display heterogeneity in the clinical presentation and underlying genetic cause. The degree of inter- and intratumor genetic heterogeneity has not yet been defined.

    EXPERIMENTAL DESIGN: In PPGLs from 94 patients, we analyzed LOH, copy-number variations, and mutation status of SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, NF1, RET, TMEM127, MAX, and HRAS using high-density SNP array and targeted deep sequencing, respectively. Genetic heterogeneity was determined through (i) bioinformatics analysis of individual samples that estimated absolute purity and ploidy from SNP array data and (ii) comparison of paired tumor samples that allowed reconstruction of phylogenetic trees.

    RESULTS: Mutations were found in 61% of the tumors and correlated with specific patterns of somatic copy-number aberrations (SCNA) and degree of nontumoral cell admixture. Intratumor genetic heterogeneity was observed in 74 of 136 samples using absolute bioinformatics estimations and in 22 of 24 patients by comparison of paired samples. In addition, a low genetic concordance was observed between paired primary tumors and distant metastases. This allowed for reconstructing the life history of individual tumors, identifying somatic mutations as well as copy-number loss of 3p and 11p (VHL subgroup), 1p (Cluster 2), and 17q (NF1 subgroup) as early events in PPGL tumorigenesis.

    CONCLUSIONS: Genomic landscapes of PPGL are specific to mutation subtype and characterized by genetic heterogeneity both within and between tumor lesions of the same patient.

  • 4.
    de Ståhl, Teresita Diaz
    et al.
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Pathol & Canc Diagnost, Stockholm, Sweden..
    Shamikh, Alia
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Pathol & Canc Diagnost, Stockholm, Sweden..
    Mayrhofer, Markus
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution.
    Juhos, Szilvester
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Basmaci, Elisa
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Prochazka, Gabriela
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Garcia, Maxime
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Somarajan, Praveen Raj
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Zielinska-Chomej, Katarzyna
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    Illies, Christopher
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Pathol & Canc Diagnost, Stockholm, Sweden..
    Öra, Ingrid
    Skane Univ Hosp Lund, Dept Paediat Haematol Oncol & Immunol, Lund, Sweden..
    Siesjö, Peter
    Lund Univ, Skane Univ Hosp, Dept Clin Sci Lund, Dept Neurosurg, Lund, Sweden..
    Sandström, Per-Erik
    Umeå Univ, Dept Clin Sci, Pediat, Umeå, Sweden..
    Stenman, Jakob
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Stockholm, Sweden..
    Sabel, Magnus
    Sahlgrens Univ Hosp, Queen Silv Childrens Hosp, Childhood Canc Ctr, Gothenburg, Sweden..
    Gustavsson, Bengt
    Karolinska Univ Hosp, Dept Neurosurg, Stockholm, Sweden..
    Kogner, Per
    Karolinska Inst, Dept Womens & Childrens Hlth, Childhood Canc Res Unit, Stockholm, Sweden..
    Pfeifer, Susan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncology research with a special focus on side effects.
    Ljungman, Gustaf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncology research with a special focus on side effects.
    Sandgren, Johanna
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden.;Karolinska Univ Hosp, Clin Pathol & Canc Diagnost, Stockholm, Sweden..
    Nistér, Monica
    Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden..
    The Swedish childhood tumor biobank: systematic collection and molecular characterization of all pediatric CNS and other solid tumors in Sweden2023In: Journal of Translational Medicine, ISSN 1479-5876, E-ISSN 1479-5876, Vol. 21, article id 342Article in journal (Refereed)
    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.

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  • 5.
    Mansouri, Larry
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Gunnarsson, Rebeqa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Sutton, Lesley-Ann
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hooper, Sean D.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Juliusson, Gunnar
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Hematology and Immunology.
    Next generation RNA-sequencing in prognostic subsets of chronic lymphocytic leukemia2012In: American Journal of Hematology, ISSN 0361-8609, E-ISSN 1096-8652, Vol. 87, no 7, p. 737-740Article in journal (Refereed)
    Abstract [en]

    Advances in next-generation RNA-sequencing have revealed the complexity of transcriptomes by allowing both coding and noncoding (nc) RNAs to be analyzed. However, limited data exist regarding the whole transcriptional landscape of chronic lymphocytic leukemia (CLL). In this pilot-study, we evaluated RNA-sequencing in CLL by comparing two subsets which carry almost identical or `` stereotyped'' B-cell receptors with distinct clinical outcome, that is the poor-prognostic subset # 1 (n = 4) and the more favorable-prognostic subset # 4 (n = 4). Our analysis revealed that 156 genes (e.g. LPL, WNT9A) and 76 ncRNAs, (e. g. SNORD48, SNORD115) were differentially expressed between the subsets. This technology also enabled us to identify numerous subset-specific splice variants (n = 406), which were predominantly expressed in subset # 1, including a splice-isoform of MSI2 with a novel start exon. A further important application of RNA-sequencing was for mutation detection and revealed 16-30 missense mutations per sample; notably many of these changes were found in genes with a strong potential for involvement in CLL pathogenesis, e. g., ATM and NOTCH2. This study not only demonstrates the effectiveness of RNA-sequencing for identifying mutations, quantifying gene expression and detecting splicing events, but also highlights the potential such global approaches have to significantly advance our understanding of the molecular mechanisms behind CLL development. 

  • 6.
    Mathot, Lucy
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Kundu, Snehangshu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ljungström, Viktor
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Svedlund, Jessica
    Moens, Lotte
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Adlerteg, Tom
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Falk-Sörqvist, Elin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Rendo, Verónica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bellomo, Claudia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Cortina, Carme
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Batlle, Eduard
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nilsson, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Solna.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer2017In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 77, no 7, p. 1730-1740Article in journal (Refereed)
    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.

  • 7.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Copy Number Analysis of Cancer2015Doctoral 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.

    List of papers
    1. Allele-specific copy number analysis of tumor samples with aneuploidy and tumor heterogeneity
    Open this publication in new window or tab >>Allele-specific copy number analysis of tumor samples with aneuploidy and tumor heterogeneity
    Show others...
    2011 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 12, no 10, p. R108-Article in journal (Refereed) Published
    Abstract [en]

    We describe a bioinformatic tool, Tumor Aberration Prediction Suite (TAPS), for the identification of allele-specific copy numbers in tumor samples using data from Affymetrix SNP arrays. It includes detailed visualization of genomic segment characteristics and iterative pattern recognition for copy number identification, and does not require patient-matched normal samples. TAPS can be used to identify chromosomal aberrations with high sensitivity even when the proportion of tumor cells is as low as 30%. Analysis of cancer samples indicates that TAPS is well suited to investigate samples with aneuploidy and tumor heterogeneity, which is commonly found in many types of solid tumors.

    National Category
    Bioinformatics and Systems Biology
    Research subject
    Bioinformatics
    Identifiers
    urn:nbn:se:uu:diva-164141 (URN)10.1186/gb-2011-12-10-r108 (DOI)000301176900011 ()22023820 (PubMedID)
    Available from: 2011-12-16 Created: 2011-12-16 Last updated: 2018-02-01Bibliographically approved
    2. Loss-of-heterozygosity on chromosome 19q in early-stage serous ovarian cancer is associated with recurrent disease
    Open this publication in new window or tab >>Loss-of-heterozygosity on chromosome 19q in early-stage serous ovarian cancer is associated with recurrent disease
    Show others...
    2012 (English)In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, p. 407-Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Ovarian cancer is a heterogeneous disease and prognosis for apparently similar cases of ovarian cancer varies. Recurrence of the disease in early stage (FIGO-stages I-II) serous ovarian cancer results in survival that is comparable to those with recurrent advanced-stage disease. The aim of this study was to investigate if there are specific genomic aberrations that may explain recurrence and clinical outcome.

    METHODS:

    Fifty-one women with early stage serous ovarian cancer were included in the study. DNA was extracted from formalin fixed samples containing tumor cells from ovarian tumors. Tumor samples from thirty-seven patients were analysed for allele-specific copy numbers using OncoScan single nucleotide polymorphism arrays from Affymetrix and the bioinformatic tool Tumor Aberration Prediction Suite. Genomic gains, losses, and loss-of-heterozygosity that associated with recurrent disease were identified.

    RESULTS:

    The most significant differences (p < 0.01) in Loss-of-heterozygosity (LOH) were identified in two relatively small regions of chromosome 19; 8.0-8,8 Mbp (19 genes) and 51.5-53.0 Mbp (37 genes). Thus, 56 genes on chromosome 19 were potential candidate genes associated with clinical outcome. LOH at 19q (51-56 Mbp) was associated with shorter disease-free survival and was an independent prognostic factor for survival in a multivariate Cox regression analysis. In particular LOH on chromosome 19q (51-56 Mbp) was significantly (p < 0.01) associated with loss of TP53 function.

    CONCLUSIONS:

    The results of our study indicate that presence of two aberrations in TP53 on 17p and LOH on 19q in early stage serous ovarian cancer is associated with recurrent disease. Further studies related to the findings of chromosomes 17 and 19 are needed to elucidate the molecular mechanism behind the recurring genomic aberrations and the poor clinical outcome.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-186137 (URN)10.1186/1471-2407-12-407 (DOI)000311048400001 ()22967087 (PubMedID)
    Available from: 2012-11-28 Created: 2012-11-28 Last updated: 2017-12-07Bibliographically approved
    3. Patchwork: allele-specific copy number analysis of whole-genome sequenced tumor tissue
    Open this publication in new window or tab >>Patchwork: allele-specific copy number analysis of whole-genome sequenced tumor tissue
    2013 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, no 3, p. R24-Article in journal (Refereed) Published
    Abstract [en]

    Whole-genome sequencing of tumor tissue has the potential to provide comprehensive characterization of genomic alterations in tumor samples. We present Patchwork, a new bioinformatic tool for allele-specific copy number analysis using whole-genome sequencing data. Patchwork can be used to determine the copy number of homologous sequences throughout the genome, even in aneuploid samples with moderate sequence coverage and tumor cell content. No prior knowledge of average ploidy or tumor cell content is required. Patchwork is freely available as an R package, installable via R-Forge (http://patchwork.r-forge.r-project.org/).

    Keywords
    Cancer, allele-specific copy number analysis, whole-genome sequencing, aneuploidy, tumor heterogeneity, chromothripsis
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-215306 (URN)10.1186/gb-2013-14-3-r24 (DOI)000328193700004 ()
    Available from: 2014-01-13 Created: 2014-01-13 Last updated: 2017-12-06Bibliographically approved
    4. 1p36 deletion is a marker for tumour dissemination in microsatellite stable stage II-III colon cancer
    Open this publication in new window or tab >>1p36 deletion is a marker for tumour dissemination in microsatellite stable stage II-III colon cancer
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    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: 2022-01-28Bibliographically approved
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  • 8.
    Mayrhofer, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    DiLorenzo, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Patchwork: allele-specific copy number analysis of whole-genome sequenced tumor tissue2013In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, no 3, p. R24-Article in journal (Refereed)
    Abstract [en]

    Whole-genome sequencing of tumor tissue has the potential to provide comprehensive characterization of genomic alterations in tumor samples. We present Patchwork, a new bioinformatic tool for allele-specific copy number analysis using whole-genome sequencing data. Patchwork can be used to determine the copy number of homologous sequences throughout the genome, even in aneuploid samples with moderate sequence coverage and tumor cell content. No prior knowledge of average ploidy or tumor cell content is required. Patchwork is freely available as an R package, installable via R-Forge (http://patchwork.r-forge.r-project.org/).

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    fulltext
  • 9.
    Mayrhofer, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Epidemiol & Biostat, Nobels Vag 12A, SE-17177 Stockholm, Sweden.
    Viklund, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Isaksson, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Rawcopy: Improved copy number analysis with Affymetrix arrays2016In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, article id 36158Article in journal (Refereed)
    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.

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  • 10. Mengelbier, Linda Holmquist
    et al.
    Karlsson, Jenny
    Lindgren, David
    Valind, Anders
    Lilljebjorn, Henrik
    Jansson, Caroline
    Bexell, Daniel
    Braekeveldt, Noemie
    Ameur, Adam
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Jonson, Tord
    Kultima, Hanna Göransson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Asmundsson, Jurate
    Versteeg, Rogier
    Rissler, Marianne
    Fioretos, Thoas
    Sandstedt, Bengt
    Borjesson, Anna
    Backman, Torbjorn
    Pal, Niklas
    Ora, Ingrid
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Gisselsson, David
    Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer2015In: Nature Communications, E-ISSN 2041-1723, Vol. 6, article id 6125Article in journal (Refereed)
    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.

  • 11.
    Rasmussen, Markus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sundström, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Kultima, Hanna Göransson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Botling, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Micke, Patrick
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Colorectal Surgery.
    Glimelius, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Allele-specific copy number analysis of tumor samples with aneuploidy and tumor heterogeneity2011In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 12, no 10, p. R108-Article in journal (Refereed)
    Abstract [en]

    We describe a bioinformatic tool, Tumor Aberration Prediction Suite (TAPS), for the identification of allele-specific copy numbers in tumor samples using data from Affymetrix SNP arrays. It includes detailed visualization of genomic segment characteristics and iterative pattern recognition for copy number identification, and does not require patient-matched normal samples. TAPS can be used to identify chromosomal aberrations with high sensitivity even when the proportion of tumor cells is as low as 30%. Analysis of cancer samples indicates that TAPS is well suited to investigate samples with aneuploidy and tumor heterogeneity, which is commonly found in many types of solid tumors.

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  • 12.
    Skírnisdóttir, Ingiridur
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Mayrhofer, Markus
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Rydåker, Maria
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Åkerud, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology.
    Isaksson, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Loss-of-heterozygosity on chromosome 19q in early-stage serous ovarian cancer is associated with recurrent disease2012In: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, p. 407-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Ovarian cancer is a heterogeneous disease and prognosis for apparently similar cases of ovarian cancer varies. Recurrence of the disease in early stage (FIGO-stages I-II) serous ovarian cancer results in survival that is comparable to those with recurrent advanced-stage disease. The aim of this study was to investigate if there are specific genomic aberrations that may explain recurrence and clinical outcome.

    METHODS:

    Fifty-one women with early stage serous ovarian cancer were included in the study. DNA was extracted from formalin fixed samples containing tumor cells from ovarian tumors. Tumor samples from thirty-seven patients were analysed for allele-specific copy numbers using OncoScan single nucleotide polymorphism arrays from Affymetrix and the bioinformatic tool Tumor Aberration Prediction Suite. Genomic gains, losses, and loss-of-heterozygosity that associated with recurrent disease were identified.

    RESULTS:

    The most significant differences (p < 0.01) in Loss-of-heterozygosity (LOH) were identified in two relatively small regions of chromosome 19; 8.0-8,8 Mbp (19 genes) and 51.5-53.0 Mbp (37 genes). Thus, 56 genes on chromosome 19 were potential candidate genes associated with clinical outcome. LOH at 19q (51-56 Mbp) was associated with shorter disease-free survival and was an independent prognostic factor for survival in a multivariate Cox regression analysis. In particular LOH on chromosome 19q (51-56 Mbp) was significantly (p < 0.01) associated with loss of TP53 function.

    CONCLUSIONS:

    The results of our study indicate that presence of two aberrations in TP53 on 17p and LOH on 19q in early stage serous ovarian cancer is associated with recurrent disease. Further studies related to the findings of chromosomes 17 and 19 are needed to elucidate the molecular mechanism behind the recurring genomic aberrations and the poor clinical outcome.

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  • 13.
    Stratmann, Svea
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Yones, Sara A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Garbulowski, Mateusz
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sun, Jitong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Skaftason, Aron
    Department of Molecular Medicine and Surgery; Karolinska Institutet, Stockholm, Sweden.
    Mayrhofer, Markus
    Uppsala University, Science for Life Laboratory, SciLifeLab. National Bioinformatics Infrastructure Sweden.
    Norgren, Nina
    Department of Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Umeå University, Sweden.
    Herlin, Morten K.
    Department of Clinical Medicine - Department of Pediatrics and Adolescent Medicine, Aarhus University, Denmark.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palle, J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Abrahamsson, Jonas
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Jahnukainen, Kirsi
    Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Cheng Munthe-Kaas, Monica
    Norwegian Institute of Public Health, Oslo, Norway; Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Zeller, Bernward
    Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Tamm, Katja P.
    Department of Oncology and Pathology, Karolinska Institutet and Karolinska University hospital, Sweden.
    Cavelier, Lucia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Swedish Collegium for Advanced Study (SCAS). The Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland; Washington National Primate Research Center, Seattle, WA, USA.
    Holmfeldt, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. The Beijer Laboratory, Uppsala, Sweden.
    SUPPLEMENTAL INFORMATION FOR: Transcriptomic analysis reveals pro-inflammatory signatures associated with acute myeloid leukemia progression2020Data set
  • 14.
    Stratmann, Svea
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Yones, Sara A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Garbulowski, Mateusz
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Sun, Jitong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Skaftason, Aron
    Department of Molecular Medicine and Surgery; Karolinska Institutet, Stockholm, Sweden.
    Mayrhofer, Markus
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Norgren, Nina
    Department of Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Umeå University, Sweden.
    Herlin, Morten Krogh
    Department of Clinical Medicine - Department of Pediatrics and Adolescent Medicine, Aarhus University, Denmark.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology. Department of Medical Sciences, Uppsala University, Sweden.
    Palle, Josefine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Neuropediatrics/Paediatric oncology.
    Abrahamsson, Jonas
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Jahnukainen, Kirsi
    Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Munthe-Kaas, Monica Cheng
    Norwegian Institute of Public Health, Oslo, Norway.
    Zeller, Bernward
    Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Tamm, Katja Pokrovskaja
    Department of Oncology and Pathology, Karolinska Institutet and Karolinska University hospital, Sweden.
    Cavelier, Lucia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Swedish Collegium for Advanced Study (SCAS). Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland.; Washington National Primate Research Center, Seattle, WA, USA..
    Holmfeldt, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. The Beijer Laboratory, Uppsala, Sweden..
    SUPPLEMENTARY MATERIAL: Transcriptomic analysis reveals pro-inflammatory signatures associated with acute myeloid leukemia progression2021Data set
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    Supplementary tables
  • 15.
    Stratmann, Svea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Yones, Sara A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Garbulowski, Mateusz
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sun, Jitong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Skaftason, Aron
    Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    Mayrhofer, Markus
    Uppsala University, Science for Life Laboratory, SciLifeLab. National Bioinformatics Infrastructure Sweden.
    Norgren, Nina
    Department of Molecular Biology, National Bioinformatics Infrastructure Sweden; Science for Life Laboratory, Umeå University, Sweden.
    Krogh Herlin, Morten
    Department of Clinical Medicine, Department of Pediatrics and Adolescent Medicine, Aarhus University, Denmark.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatric oncological and neurological research.
    Abrahamsson, Jonas
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Jahnukainen, Kirsi
    Children's Hospital, University of Helsinki; Helsinki University Central Hospital, Helsinki, Finland.
    Cheng Munthe-Kaas, Monica
    Norwegian Institute of Public Health, Oslo, Norway; Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Zeller, Bernward
    Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Pokrovskaja Tamm, Katja
    Department of Oncology and Pathology, Karolinska Institutet; Karolinska University Hospital, Sweden.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Swedish Collegium for Advanced Study (SCAS). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health. The Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland; Washington National Primate Research Center, Seattle, WA, USA; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; Department of Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Umeå University, Umeå, Sweden; Department of Clinical Medicine and Department of Pediatrics and Adolescent Medicine, Aarhus University, Aarhus, Denmark; Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden; Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Norwegian Institute of Public Health, Oslo, Norway; Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway; Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
    Holmfeldt, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Transcriptomic analysis reveals proinflammatory signatures associated with acute myeloid leukemia progression2022In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 6, no 1, p. 152-164Article in journal (Refereed)
    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.

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  • 16.
    Stratmann, Svea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Yones, Sara A.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mayrhofer, Markus
    Uppsala University, Science for Life Laboratory, SciLifeLab. National Bioinformatics Infrastructure Sweden.
    Norgren, Nina
    Department of Molecular Biology, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Umeå University, Sweden.
    Skaftason, Aron
    Department of Molecular Medicine and Surgery; Karolinska Institutet, Stockholm, Sweden.
    Sun, Jitong
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Smolinska, Karolina
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Swedish Collegium for Advanced Study (SCAS). The Institute of Computer Science, Polish Academy of Sciences, Warsaw, Poland; Washington National Primate Research Center, Seattle, WA, USA.
    Krogh Herlin, Morten
    Department of Clinical Medicine and Department of Pediatrics and Adolescent Medicine, Aarhus University, Denmark.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Eriksson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Palle, Josefine
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Neuropediatrics/Paediatric oncology.
    Abrahamsson, Jonas
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Jahnukainen, Kirsi
    Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
    Cheng Munthe-Kaas, Monica
    Norwegian Institute of Public Health, Oslo, Norway; Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Zeller, Bernward
    Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
    Pokrovskaja Tamm, Katja
    Department of Oncology and Pathology, Karolinska Institutet and Karolinska University hospital, Sweden.
    Cavelier, Lucia
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Holmfeldt, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab. The Beijer Laboratory, Uppsala, Sweden.
    Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets2021In: Blood Advances, ISSN 2473-9529 , E-ISSN 2473-9537, Vol. 5, no 3, p. 900-912Article in journal (Refereed)
    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.

  • 17.
    Walther, Charles
    et al.
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nilsson, Jenny
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Hofvander, Jakob
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Jonson, Tord
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Mandahl, Nils
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Ora, Ingrid
    Skane Univ Hosp, Dept Pediat Oncol, S-22185 Lund, Sweden..
    Gisselsson, David
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Mertens, Fredrik
    Lund Univ, Skane Univ Hosp, Univ & Reg Labs, Dept Clin Genet, Lund, Sweden..
    Genetic Heterogeneity in Rhabdomyosarcoma Revealed by SNP Array Analysis2016In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 55, no 1, p. 3-15Article in journal (Refereed)
    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.

  • 18. Watkins, Johnathan
    et al.
    Weekes, Daniel
    Shah, Vandna
    Gazinska, Patrycja
    Joshi, Shalaka
    Sidhu, Bhavna
    Gillett, Cheryl
    Pinder, Sarah
    Vanoli, Fabio
    Jasin, Maria
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Isaksson, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Cheang, Maggie C. U.
    Mirza, Hasan
    Frankum, Jessica
    Lord, Christopher J.
    Ashworth, Alan
    Vinayak, Shaveta
    Ford, James M.
    Telli, Melinda L.
    Grigoriadis, Anita
    Tutt, Andrew N. J.
    Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers2015In: Cancer Discovery, ISSN 2159-8274, E-ISSN 2159-8290, Vol. 5, no 5, p. 488-505Article in journal (Refereed)
    Abstract [en]

    Triple-negative breast cancers (TNBC) are characterized by a wide spectrum of genomic alterations, some of which might be caused by defects in DNA repair processes such as homologous recombination (HR). Despite this understanding, associating particular patterns of genomic instability with response to therapy has been challenging. Here, we show that allelic-imbalanced copy-number aberrations (AiCNA) are more prevalent in TNBCs that respond to platinum-based chemotherapy, thus providing a candidate predictive biomarker for this disease. Furthermore, we show that a high level of AiCNA is linked with elevated expression of a meiosis-associated gene, HORMAD1. Elevated HORMAD1 expression suppresses RAD51-dependent HR and drives the use of alternative forms of DNA repair, the generation of AiCNAs, as well as sensitizing cancer cells to HR-targeting therapies. Our data therefore provide a mechanistic association between HORMAD1 expression, a specific pattern of genomic instability, and an association with response to platinum-based chemotherapy in TNBC. SIGNIFICANCE: Previous studies have shown correlation between mutational "scars" and sensitivity to platinums extending beyond associations with BRCA1/2 mutation, but do not elucidate the mechanism. Here, a novel allele-specific copy-number characterization of genome instability identifies and functionally validates the inappropriate expression of the meiotic gene HORMAD1 as a driver of HR deficiency in TNBC, acting to induce allelic imbalance and moderate platinum and PARP inhibitor sensitivity with implications for the use of such "scars" and expression of meiotic genes as predictive biomarkers.

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