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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
Öppna denna publikation i ny flik eller fönster >>Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages
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2018 (Engelska)Ingår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, nr 8, s. 1080-1091Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
OXFORD UNIV PRESS INC, 2018
Nyckelord
aneuploidy, clones, GBM DNA methylation, GBM subtype, glioma stem cell cultures, patient derived GBM cell cultures, systems biology
Nationell ämneskategori
Cell- och molekylärbiologi
Identifikatorer
urn:nbn:se:uu:diva-361042 (URN)10.1093/neuonc/noy024 (DOI)000438338000009 ()29462414 (PubMedID)
Forskningsfinansiär
Vetenskapsrådet, 2014-03314Cancerfonden, CAN 2017/628Stiftelsen för strategisk forskning (SSF), BD15-088
Tillgänglig från: 2018-09-20 Skapad: 2018-09-20 Senast uppdaterad: 2018-09-20Bibliografiskt granskad
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
Öppna denna publikation i ny flik eller fönster >>Genetic Heterogeneity in Rhabdomyosarcoma Revealed by SNP Array Analysis
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2016 (Engelska)Ingår i: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 55, nr 1, s. 3-15Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Cancer och onkologi Medicinsk genetik
Identifikatorer
urn:nbn:se:uu:diva-276867 (URN)10.1002/gcc.22285 (DOI)000368259400001 ()26482321 (PubMedID)
Forskningsfinansiär
Barncancerfonden
Tillgänglig från: 2016-02-16 Skapad: 2016-02-16 Senast uppdaterad: 2018-01-10Bibliografiskt granskad
Mayrhofer, M., Viklund, B. & Isaksson, A. (2016). Rawcopy: Improved copy number analysis with Affymetrix arrays. Scientific Reports, 6, Article ID 36158.
Öppna denna publikation i ny flik eller fönster >>Rawcopy: Improved copy number analysis with Affymetrix arrays
2016 (Engelska)Ingår i: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, artikel-id 36158Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Biomedicinsk laboratorievetenskap/teknologi
Identifikatorer
urn:nbn:se:uu:diva-308636 (URN)10.1038/srep36158 (DOI)000386461800001 ()27796336 (PubMedID)
Forskningsfinansiär
Cancerfonden
Tillgänglig från: 2016-11-30 Skapad: 2016-11-29 Senast uppdaterad: 2017-11-29Bibliografiskt granskad
Mayrhofer, M. (2015). Copy Number Analysis of Cancer. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Öppna denna publikation i ny flik eller fönster >>Copy Number Analysis of Cancer
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2015. s. 42
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1072
Nyckelord
chromosomes, oncology, bioinformatics
Nationell ämneskategori
Bioinformatik (beräkningsbiologi) Genetik Cancer och onkologi Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Forskningsämne
Bioinformatik; Onkologi; Klinisk genetik
Identifikatorer
urn:nbn:se:uu:diva-244361 (URN)978-91-554-9175-8 (ISBN)
Disputation
2015-04-17, BMC E10:1307-1309, BMC, Husargatan 3, Uppsala, 13:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-03-26 Skapad: 2015-02-16 Senast uppdaterad: 2018-01-11
Watkins, J., Weekes, D., Shah, V., Gazinska, P., Joshi, S., Sidhu, B., . . . Tutt, A. N. J. (2015). Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers. Cancer Discovery, 5(5), 488-505
Öppna denna publikation i ny flik eller fönster >>Genomic Complexity Profiling Reveals That HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-Negative Breast Cancers
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2015 (Engelska)Ingår i: Cancer Discovery, ISSN 2159-8274, E-ISSN 2159-8290, Vol. 5, nr 5, s. 488-505Artikel i tidskrift (Refereegranskat) Published
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.

Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-253235 (URN)10.1158/2159-8290.CD-14-1092 (DOI)000353700000022 ()25770156 (PubMedID)
Tillgänglig från: 2015-06-22 Skapad: 2015-05-25 Senast uppdaterad: 2017-12-04Bibliografiskt granskad
Mengelbier, L. H., Karlsson, J., Lindgren, D., Valind, A., Lilljebjorn, H., Jansson, C., . . . Gisselsson, D. (2015). Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer. Nature Communications, 6, Article ID 6125.
Öppna denna publikation i ny flik eller fönster >>Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer
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2015 (Engelska)Ingår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 6, artikel-id 6125Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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

Nationell ämneskategori
Medicinsk genetik Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-246672 (URN)10.1038/ncomms7125 (DOI)000348832000001 ()25625758 (PubMedID)
Tillgänglig från: 2015-03-18 Skapad: 2015-03-09 Senast uppdaterad: 2018-01-11Bibliografiskt granskad
Birgisson, H., Edlund, K., Wallin, U., Påhlman, L., Kultima, H. G., Mayrhofer, M., . . . Sundström, M. (2015). Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer. BMC Cancer, 15, Article ID 125.
Öppna denna publikation i ny flik eller fönster >>Microsatellite instability and mutations in BRAF and KRAS are significant predictors of disseminated disease in colon cancer
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2015 (Engelska)Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 15, artikel-id 125Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

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

Nyckelord
Colon cancer, MSI, BRAF, KRAS, PIK3CA, DNA copy number, Prognosis
Nationell ämneskategori
Cancer och onkologi
Identifikatorer
urn:nbn:se:uu:diva-251424 (URN)10.1186/s12885-015-1144-x (DOI)000351047900001 ()
Tillgänglig från: 2015-04-23 Skapad: 2015-04-17 Senast uppdaterad: 2018-02-01Bibliografiskt granskad
Crona, J., Backman, S., Maharjan, R., Mayrhofer, M., Stålberg, P., Isaksson, A., . . . Björklund, P. (2015). Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis.. Clinical Cancer Research, 21(19), 4451-4460
Öppna denna publikation i ny flik eller fönster >>Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis.
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2015 (Engelska)Ingår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, nr 19, s. 4451-4460Artikel i tidskrift (Refereegranskat) Published
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.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-266641 (URN)10.1158/1078-0432.CCR-14-2854 (DOI)000363330500027 ()25991818 (PubMedID)
Forskningsfinansiär
Cancerfonden
Tillgänglig från: 2015-11-10 Skapad: 2015-11-10 Senast uppdaterad: 2019-10-30Bibliografiskt granskad
Mayrhofer, M., DiLorenzo, S. & Isaksson, A. (2013). Patchwork: allele-specific copy number analysis of whole-genome sequenced tumor tissue. Genome Biology, 14(3), R24
Öppna denna publikation i ny flik eller fönster >>Patchwork: allele-specific copy number analysis of whole-genome sequenced tumor tissue
2013 (Engelska)Ingår i: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 14, nr 3, s. R24-Artikel i tidskrift (Refereegranskat) 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/).

Nyckelord
Cancer, allele-specific copy number analysis, whole-genome sequencing, aneuploidy, tumor heterogeneity, chromothripsis
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-215306 (URN)10.1186/gb-2013-14-3-r24 (DOI)000328193700004 ()
Tillgänglig från: 2014-01-13 Skapad: 2014-01-13 Senast uppdaterad: 2017-12-06Bibliografiskt granskad
Skírnisdóttir, I., Mayrhofer, M., Rydåker, M., Åkerud, H. & Isaksson, A. (2012). Loss-of-heterozygosity on chromosome 19q in early-stage serous ovarian cancer is associated with recurrent disease. BMC Cancer, 12, 407
Öppna denna publikation i ny flik eller fönster >>Loss-of-heterozygosity on chromosome 19q in early-stage serous ovarian cancer is associated with recurrent disease
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2012 (Engelska)Ingår i: BMC Cancer, ISSN 1471-2407, E-ISSN 1471-2407, Vol. 12, s. 407-Artikel i tidskrift (Refereegranskat) 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.

Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
urn:nbn:se:uu:diva-186137 (URN)10.1186/1471-2407-12-407 (DOI)000311048400001 ()22967087 (PubMedID)
Tillgänglig från: 2012-11-28 Skapad: 2012-11-28 Senast uppdaterad: 2017-12-07Bibliografiskt granskad
Organisationer
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0003-3403-0083

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