| 1. |
- Gisselsson Nord, David, et al.
(author)
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Generation of trisomies in cancer cells by multipolar mitosis and incomplete cytokinesis.
- 2010
-
In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 107:47, s. 20489-20493
-
Journal article (peer-reviewed)abstract
- One extra chromosome copy (i.e., trisomy) is the most common type of chromosome aberration in cancer cells. The mechanisms behind the generation of trisomies in tumor cells are largely unknown, although it has been suggested that dysfunction of the spindle assembly checkpoint (SAC) leads to an accumulation of trisomies through failure to correctly segregate sister chromatids in successive cell divisions. By using Wilms tumor as a model for cancers with trisomies, we now show that trisomic cells can form even in the presence of a functional SAC through tripolar cell divisions in which sister chromatid separation proceeds in a regular fashion, but cytokinesis failure nevertheless leads to an asymmetrical segregation of chromosomes into two daughter cells. A model for the generation of trisomies by such asymmetrical cell division accurately predicted several features of clones having extra chromosomes in vivo, including the ratio between trisomies and tetrasomies and the observation that different trisomies found in the same tumor occupy identical proportions of cells and colocalize in tumor tissue. Our findings provide an experimentally validated model explaining how multiple trisomies can occur in tumor cells that still maintain accurate sister chromatid separation at metaphase-anaphase transition and thereby physiologically satisfy the SAC.
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| 2. |
- Snape, Katie, et al.
(author)
-
Mutations in CEP57 cause mosaic variegated aneuploidy syndrome
- 2011
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:6, s. 527-529
-
Journal article (peer-reviewed)abstract
- Using exome sequencing and a variant prioritization strategy that focuses on loss-of-function variants, we identified biallelic, loss-of-function CEP57 mutations as a cause of constitutional mosaic aneuploidies. CEP57 is a centrosomal protein and is involved in nucleating and stabilizing microtubules. Our findings indicate that these and/or additional functions of CEP57 are crucial for maintaining correct chromosomal number during cell division.
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| 3. |
- Braekeveldt, Noémie, et al.
(author)
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Patient-derived xenograft models reveal intratumor heterogeneity and temporal stability in neuroblastoma
- 2018
-
In: Cancer Research. - 0008-5472. ; 78:20, s. 5958-5969
-
Journal article (peer-reviewed)abstract
- Patient-derived xenografts (PDX) and the Avatar, a single PDX mirroring an individual patient, are emerging tools in preclinical cancer research. However, the consequences of intratumor heterogeneity for PDX modeling of biomarkers, target identification, and treatment decisions remain underexplored. In this study, we undertook serial passaging and comprehensive molecular analysis of neuroblastoma orthotopic PDXs, which revealed strong intrinsic genetic, transcriptional, and phenotypic stability for more than 2 years. The PDXs showed preserved neuroblastoma-associated gene signatures that correlated with poor clinical outcome in a large cohort of patients with neuroblastoma. Furthermore, we captured spatial intratumor heterogeneity using ten PDXs from a single high-risk patient tumor. We observed diverse growth rates, transcriptional, proteomic, and phosphoproteomic profiles. PDX-derived transcriptional profiles were associated with diverse clinical characteristics in patients with high-risk neuroblastoma. These data suggest that high-risk neuroblastoma contains elements of both temporal stability and spatial intratumor heterogeneity, the latter of which complicates clinical translation of personalized PDX-Avatar studies into preclinical cancer research.
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| 4. |
- Gisselsson Nord, David, et al.
(author)
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Genetic bottlenecks and the hazardous game of population reduction in cell line based research.
- 2010
-
In: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 316, s. 3379-3386
-
Journal article (peer-reviewed)abstract
- Established tumour cell lines are ubiquitous tools in research, but their representativity is often debated. One possible caveat is that many cell lines are derived from cells with genomic instability, potentially leading to genotype changes in vitro. We applied SNP-array analysis to an established tumour cell line (WiT49). Even though WiT49 exhibited chromosome segregation errors in 30% of cell divisions, only a single chromosome segment exhibited a shift in copy number after 20 population doublings in culture. In contrast, sub-populations derived from single cells expanded for an equal number of population doublings showed on average 5.8 and 8.9 altered segments compared to the original culture and to each other, respectively. Most copy number variants differentiating these single cell clones corresponded to pre-existing variations in the original culture. Furthermore, no sub-clonal variation was detected in any of the populations derived from single cells. This indicates that genetic bottlenecks resulting from population reduction poses a higher threat to genetic representativity than prolonged culture per se, even in cell lines with a high rate of genomic instability. Genetic bottlenecks should therefore be considered a potential caveat in all studies involving sub-cloning, transfection and other conditions leading to a temporary reduction in cell number.
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| 5. |
- Holmquist Mengelbier, Linda, et al.
(author)
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Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster.
- 2010
-
In: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 177:5, s. 2609-2621
-
Journal article (peer-reviewed)abstract
- Wilms tumor is the most common pediatric renal neoplasm, but few molecular prognostic markers have been identified for this tumor. Somatic deletion in the long arm of chromosome 16 (16q) is known to predict a less favorable outcome in Wilms tumor, but the underlying molecular mechanisms are not known. We show that 16q deletions are typically confined to immature anaplastic-blastic tumor elements, while deletions are absent in maturing tumor components. The smallest region of deletion overlap mapped to a 1.8-Mb segment containing the IRXB gene cluster including IRX3, IRX5, and IRX6, of which IRX3 is a recently identified regulator of tubular maturation during nephrogenesis. Tumors with 16q deletion showed a lower overall mRNA expression of IRXB genes, and 16q-deleted tumor cells failed to express IRX3 while it was expressed in differentiating tubular tumor elements with intact 16q. Consistent with a role for IRX3 in tubular differentiation, gene sets linked to Notch signaling, Rho signaling, and ion channel activity were enriched in tumors with high IRX3 expression, while WTs with low expression were enriched for gene sets linked to cell cycle progression. Low mRNA levels of IRXB genes were associated with diffuse anaplasia, high-stage disease, and death. A disturbed balance between tubular differentiation and self-renewal of anaplastic-blastic elements may thus be one mechanism linking 16q deletion to adverse outcome in Wilms tumor.
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| 6. |
- Holmquist Mengelbier, Linda, et al.
(author)
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Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer.
- 2015
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
-
Journal article (peer-reviewed)abstract
- 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.
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| 7. |
- Jin, Yuesheng, et al.
(author)
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Distinct mitotic segregation errors mediate chromosomal instability in aggressive urothelial cancers.
- 2007
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In: Clinical Cancer Research. - 1078-0432. ; 13:6, s. 1703-1712
-
Journal article (peer-reviewed)abstract
- Purpose: Chromosomal instability (CIN) is believed to have an important role in the pathogenesis of urothelial cancer (UC). The aim of this study was to evaluate whether disturbances of mitotic segregation contribute to CIN in UC, if these processes have any effect on the course of disease, and how deregulation of these mechanisms affects tumor cell growth. Experimental Design: We developed molecular cytogenetic methods to classify mitotic segregation abnormalities in a panel of UC cell lines. Mitotic instabilities were then scored in biopsies from 52 UC patients and compared with the outcome of tumor disease. Finally, UC cells were exposed in vitro to a telomerase inhibitor to assess how this affects mitotic stability and cell proliferation. Results: Three distinct chromosome segregation abnormalities were identified: (a) telomere dysfunction, which triggers structural rearrangements and loss of chromosomes through anaphase bridging; (b) sister chromatid nondisjunction, which generates discrete chromosomal copy number variations; and (c) supernumerary centrosomes, which cause dramatic shifts in chromosome copy number through multipolar cell division. Chromosome segregation errors were already present in preinvasive tumors and a high rate mitotic instability was an independent predictor of poor survival. However, induction of even higher levels of the same segregation abnormalities in UC cells by telomerase inhibition in vitro led to reduced tumor cell proliferation and clonogenic survival. Conclusion: Several distinct chromosome segregation errors contribute to CIN in UC, and the rate of such mitotic errors has a significant effect on the clinical course. Efficient tumor cell proliferation may depend on the tight endogenous control of these processes.
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| 8. |
- Lee, Charles, et al.
(author)
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Limitations of chromosome classification by multicolor karyotyping
- 2001
-
In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 68:4, s. 1043-1047
-
Journal article (peer-reviewed)abstract
- Multicolor karyotyping technologies, such as spectral karyotyping (SKY) (Schrock et al.1996; Liyanage et al. 1996) and multiplex (M-) FISH (Speicher et al. 1996), have proved to be extremely useful in prenatal, postnatal, and cancer cytogenetics. However, these technologies have inherent limitations that, in certain situations, may result in chromosomal misclassification. In this report, we present nine cases, which fall into five categories, in which multicolor karyotyping has produced erroneous interpretations. Most errors appear to have a similar mechanistic basis.
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| 9. |
- Pietras, Alexander, et al.
(author)
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HIF-2 alpha maintains an undifferentiated state in neural crest-like human neuroblastoma tumor-initiating cells
- 2009
-
In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 106:39, s. 16805-16810
-
Journal article (peer-reviewed)abstract
- High hypoxia-inducible factor-2 alpha (HIF-2 alpha) protein levels predict poor outcome in neuroblastoma, and hypoxia dedifferentiates cultured neuroblastoma cells toward a neural crest-like phenotype. Here, we identify HIF-2 alpha as a marker of normoxic neural crest-like neuroblastoma tumor-initiating/stem cells (TICs) isolated from patient bone marrows. Knockdown of HIF-2 alpha reduced VEGF expression and induced partial sympathetic neuronal differentiation when these TICs were grown in vitro under stem cell-promoting conditions. Xenograft tumors of HIF-2 alpha-silenced cells were widely necrotic, poorly vascularized, and resembled the bulk of tumor cells in clinical neuroblastomas by expressing additional sympathetic neuronal markers, whereas control tumors were immature, well-vascularized, and stroma-rich. Thus, HIF-2 alpha maintains an undifferentiated state of neuroblastoma TICs. Because low differentiation is associated with poor outcome and angiogenesis is crucial for tumor growth, HIF-2 alpha is an attractive target for neuroblastoma therapy.
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| 10. |
- von Stedingk, Kristoffer, et al.
(author)
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snoRNPs Regulate Telomerase Activity in Neuroblastoma and Are Associated with Poor Prognosis.
- 2013
-
In: Translational Oncology. - : Elsevier BV. - 1936-5233. ; 6:4, s. 447-457
-
Journal article (peer-reviewed)abstract
- Amplification of the MYCN oncogene is strongly associated with poor prognosis in neuroblastoma (NB). In addition to MYCN amplification, many studies have focused on identifying patients with a poor prognosis based on gene expression profiling. The majority of prognostic signatures today are comprised of large gene lists limiting their clinical application. In addition, although of prognostic significance, most of these signatures fail to identify cellular processes that can explain their relation to prognosis. Here, we determined prognostically predictive genes in a data set containing 251 NBs. Gene Ontology analysis was performed on significant genes with a positive hazard ratio to search for cellular processes associated with poor prognosis. An enrichment in ribonucleoproteins (RNPs) was found. Genes involved in the stabilization and formation of the central small nucleolar RNP (snoRNP) complex were scrutinized using a backward conditional Cox regression resulting in an snoRNP signature consisting of three genes: DKC1, NHP2, and GAR1. The snoRNP signature significantly and independently predicted prognosis when compared to the established clinical risk factors. Association of snoRNP protein expression and prognosis was confirmed using tissue micro-arrays. Knockdown of snoRNP expression in NB cell lines resulted in reduced telomerase activity and an increase in anaphase bridge frequency. In addition, in patient material, expression of the snoRNP complex was significantly associated with telomerase activity, occurrence of segmental aberrations, and expression-based measurements of chromosomal instability. Together, these results underscore the prognostic value of snoRNP complex expression in NB and suggest a role for snoRNPs in telomere maintenance and genomic stability.
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| 11. |
- Walz, Amy L., et al.
(author)
-
Tumor biology, biomarkers, and liquid biopsy in pediatric renal tumors
- 2023
-
In: Pediatric Blood and Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 70:S2
-
Research review (peer-reviewed)abstract
- The expansion of knowledge regarding driver mutations for Wilms tumor (WT) and malignant rhabdoid tumor of the kidney (MRT) and various translocations for other pediatric renal tumors opens up new possibilities for diagnosis and treatment. In addition, there are growing data surrounding prognostic factors that can be used to stratify WT treatment to improve outcomes. Here, we review the molecular landscape of WT and other pediatric renal tumors as well as WT prognostic factors. We also review incorporation of circulating tumor DNA/liquid biopsies to leverage this molecular landscape, with potential use in the future for distinguishing renal tumors at the time of diagnosis and elucidating intratumor heterogeneity, which is not well evaluated with standard biopsies. Incorporation of liquid biopsies will require longitudinal collection of multiple biospecimens. Further preclinical research, identification and validation of biomarkers, molecular studies, and data sharing among investigators are crucial to inform therapeutic strategies that improve patient outcomes.
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| 12. |
- Adem, C, et al.
(author)
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ETV6 rearrangements in patients with infantile fibrosarcomas and congenital mesoblastic nephromas by fluorescence in situ hybridization
- 2001
-
In: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 14:12, s. 1246-1251
-
Journal article (peer-reviewed)abstract
- Congenital mesoblastic nephroma (CMN) and infantile fibrosarcoma (IFS) are two pediatric tumors arising in the kidneys and soft tissues of infants, respectively. Recently, a t(12;15)(p13;q25) resulting in ETV6-NTRK3 gene fusion was detected in patients with IFS and in patients with the cellular type of CMN, suggesting a common pathogenetic pathway. We investigated the presence or absence of ETV6 rearrangements and numerical abnormalities of chromosome 11 by using fluorescence in situ hybridization on paraffin-embedded material from five cases of IFS, two of CMN, and one of mixed type (CMN and IFS) found in our files. In three cases of IFS, we found ETV6 gene rearrangement but a normal copy number of chromosome 11. One case each of IFS, the cellular type of CMN, and the mixed type (CMN and IFS) had both abnormalities. In a case of classic CMN, neither trisomy 11 nor gene rearrangement was found. It is possible that trisomy 11 is a later, nonessential event in the pathogenetic process or that this secondary aberration is associated with still-unrecognized clinical or biological characteristics. We confirmed that IFS and the cellular type of CMN are cytogenetically related and can occur synchronously in the same organ.
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| 13. |
- Andersson, Natalie, et al.
(author)
-
DEVOLUTION—A method for phylogenetic reconstruction of aneuploid cancers based on multiregional genotyping data
- 2021
-
In: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4
-
Journal article (peer-reviewed)abstract
- Phylogenetic reconstruction of cancer cell populations remains challenging. There is a particular lack of tools that deconvolve clones based on copy number aberration analyses of multiple tumor biopsies separated in time and space from the same patient. This has hampered investigations of tumors rich in aneuploidy but few point mutations, as in many childhood cancers and high-risk adult cancer. Here, we present DEVOLUTION, an algorithm for subclonal deconvolution followed by phylogenetic reconstruction from bulk genotyping data. It integrates copy number and sequencing information across multiple tumor regions throughout the inference process, provided that the mutated clone fraction for each mutation is known. We validate DEVOLUTION on data from 56 pediatric tumors comprising 253 tumor biopsies and show a robust performance on simulations of bulk genotyping data. We also benchmark DEVOLUTION to similar bioinformatic tools using an external dataset. DEVOLUTION holds the potential to facilitate insights into the development, progression, and response to treatment, particularly in tumors with high burden of chromosomal copy number alterations.
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| 14. |
- Andersson, Natalie, et al.
(author)
-
Extensive clonal branching shapes the evolutionary history of high-risk pediatric cancers
- 2020
-
In: Cancer Research. - 1538-7445. ; 80:7, s. 1512-1523
-
Journal article (peer-reviewed)abstract
- Darwinian evolution of tumor cells remains underexplored in childhood cancer. We here reconstruct the evolutionary histories of 56 pediatric primary tumors, including 24 neuroblastomas, 24 Wilms tumors and 8 rhabdomyosarcomas. Whole genome copy number and whole exome mutational profiling of multiple regions per tumor was performed followed by clonal deconvolution to reconstruct a phylogenetic tree for each tumor. Overall, 88% of the tumors exhibited genetic variation among primary tumor regions. This variability typically emerged through collateral phylogenetic branching, leading to spatial variability in the distribution of more than 50% (96/173) of detected diagnostically informative genetic aberrations. Single cell sequencing of 547 individual cancer cells from eight solid pediatric tumors confirmed branching evolution to be a fundamental underlying principle of genetic variation in all cases. Strikingly, cell-to-cell genetic diversity was almost twice as high in aggressive compared to clinically favorable tumors (median Simpson index of diversity 0.45 vs. 0.88; p=0.029). Similarly, a comparison of multiregional sampling data from a total of 274 tumor regions showed that new phylogenetic branches emerge at a higher frequency per sample and carry a higher mutational load in high-risk than in low-risk tumors. Timelines based on spatial genetic variation showed that the mutations most influencing relapse risk occur at initiation of clonal expansion in neuroblastoma and rhabdomyosarcoma, while in Wilms tumor they are late events. Thus, from an evolutionary standpoint, some high-risk childhood cancers are born bad, while others grow worse over time.
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| 15. |
- Andersson, Natalie, et al.
(author)
-
Inactivation of RB1, CDKN2A and TP53 have distinct effects on genomic stability at side-by-side comparison in karyotypically normal cells
- 2023
-
In: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 62:2, s. 93-100
-
Journal article (peer-reviewed)abstract
- Chromosomal instability is a common feature in malignant tumors. Previous studies have indicated that inactivation of the classical tumor suppressor genes RB1, CDKN2A and TP53 may contribute to chromosomal aberrations in cancer by disrupting different aspects of the cell cycle and DNA damage checkpoint machinery. We performed a side-by-side comparison of how inactivation of each of these genes affected chromosomal stability in vitro. Using CRISPR-Cas9 technology, RB1, CDKN2A and TP53 were independently knocked out in karyotypically normal immortalized cells, after which these cells were followed over time. Bulk RNA sequencing revealed a distinct phenotype with upregulation of pathways related to cell cycle control and proliferation in all three knockouts. Surprisingly, the RB1 and CDKN2A knocked out cell lines did not harbor more copy number aberrations than wild-type cells, despite culturing for months. The TP53-knocked out cells, in contrast, showed a massive amount of copy number alterations and saltatory evolution through whole genome duplication. This side-by-side comparison indicated that the effects on chromosomal stability from inactivation of RB1 and CDKN2A are negligible compared to inactivation of TP53, under the same conditions in a non-stressful environment, even though partly overlapping regulatory pathways are affected.
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| 16. |
- Bexell, Daniel, et al.
(author)
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Bone Marrow Multipotent Mesenchymal Stroma Cells Act as Pericyte-like Migratory Vehicles in Experimental Gliomas.
- 2009
-
In: Molecular Therapy. - : Elsevier BV. - 1525-0024 .- 1525-0016. ; 2008:Nov 4., s. 183-190
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Journal article (peer-reviewed)abstract
- Bone marrow-derived multipotent mesenchymal stroma cells (MSCs) have emerged as cellular vectors for gene therapy of solid cancers. We implanted enhanced green fluorescent protein-expressing rat MSCs directly into rat malignant gliomas to address their migratory capacity, phenotype, and effects on tumor neovascularization and animal survival. A single intratumoral injection of MSCs infiltrated the majority of invasive glioma extensions (72 +/- 14%) and a substantial fraction of distant tumor microsatellites (32 +/- 6%). MSC migration was highly specific for tumor tissue. Grafted MSCs integrated into tumor vessel walls and expressed pericyte markers alpha-smooth muscle actin, neuron-glia 2, and platelet-derived growth factor receptor-beta but not endothelial cell markers. The pericyte marker expression profile and perivascular location of grafted MSCs indicate that these cells act as pericytes within tumors. MSC grafting did not influence tumor microvessel density or survival of tumor-bearing animals. The antiangiogenic drug Sunitinib markedly reduced the numbers of grafted MSCs migrating within tumors. We found no MSCs within gliomas following intravenous (i.v.) injections. Thus, MSCs should be administered by intratumoral implantations rather than by i.v. injections. Intratumorally grafted pericyte-like MSCs might represent a particularly well-suited vector system for delivering molecules to affect tumor angiogenesis and for targeting cancer stem cells within the perivascular niche.Molecular Therapy (2008); doi:10.1038/mt.2008.229.
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| 17. |
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| 18. |
- Braekeveldt, Noémie, et al.
(author)
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Neuroblastoma patient-derived orthotopic xenografts reflect the microenvironmental hallmarks of aggressive patient tumours
- 2016
-
In: Cancer Letters. - : Elsevier BV. - 1872-7980 .- 0304-3835. ; 375:2, s. 384-389
-
Journal article (peer-reviewed)abstract
- Treatment of high-risk childhood neuroblastoma is a clinical challenge hampered by a lack of reliable neuroblastoma mouse models for preclinical drug testing. We have previously established invasive and metastasising patient-derived orthotopic xenografts (PDXs) from high-risk neuroblastomas that retained the genotypes and phenotypes of patient tumours. Given the important role of the tumour microenvironment in tumour progression, metastasis, and treatment responses, here we analysed the tumour microenvironment of five neuroblastoma PDXs in detail. The PDXs resembled their parent tumours and retained important stromal hallmarks of aggressive lesions including rich blood and lymphatic vascularisation, pericyte coverage, high numbers of cancer-associated fibroblasts, tumour-associated macrophages, and extracellular matrix components. Patient-derived tumour endothelial cells occasionally formed blood vessels in PDXs; however, tumour stroma was, overall, of murine origin. Lymphoid cells and lymphatic endothelial cells were found in athymic nude mice but not in NSG mice; thus, the choice of mouse strain dictates tumour microenvironmental components. The murine tumour microenvironment of orthotopic neuroblastoma PDXs reflects important hallmarks of aggressive and metastatic clinical neuroblastomas. Neuroblastoma PDXs are clinically relevant models for preclinical drug testing.
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| 19. |
- Braekeveldt, Noémie, et al.
(author)
-
Neuroblastoma Patient-Derived Orthotopic Xenografts Retain Metastatic Patterns and Geno- and Phenotypes of Patient Tumours.
- 2015
-
In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 136:5, s. 252-261
-
Journal article (peer-reviewed)abstract
- Neuroblastoma is a childhood tumour with heterogeneous characteristics and children with metastatic disease often have a poor outcome. Here we describe the establishment of neuroblastoma patient-derived xenografts (PDXs) by orthotopic implantation of viably cryopreserved or fresh tumour explants of patients with high risk neuroblastoma into immunodeficient mice. In vivo tumour growth was monitored by magnetic resonance imaging and fluorodeoxyglucose - positron emission tomography. Neuroblastoma PDXs retained the undifferentiated histology and proliferative capacity of their corresponding patient tumours. The PDXs expressed neuroblastoma markers NCAM, chromogranin A, synaptophysin and tyrosine hydroxylase. Whole genome genotyping array analyses demonstrated that PDXs retained patient-specific chromosomal aberrations such as MYCN amplification, deletion of 1p, and gain of chromosome 17q. Thus, neuroblastoma PDXs recapitulate the hallmarks of high-risk neuroblastoma in patients. PDX-derived cells were cultured in serum-free medium where they formed free-floating neurospheres, expressed neuroblastoma gene markers MYCN, CHGA, TH, SYP and NPY, and retained tumour-initiating and metastatic capacity in vivo. PDXs showed much higher degree of infiltrative growth and distant metastasis as compared to neuroblastoma SK-N-BE(2)c cell line-derived orthotopic tumours. Importantly, the PDXs presented with bone marrow involvement, a clinical feature of aggressive neuroblastoma. Thus, neuroblastoma PDXs serve as clinically relevant models for studying and targeting high-risk metastatic neuroblastoma. © 2014 Wiley Periodicals, Inc.
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| 20. |
- Bullerdiek, Jörn, et al.
(author)
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Tumors of endocrine glands
- 2015. - 4th
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In: Cancer Cytogenetics : Chromosomal and Molecular Genetic Aberrations of Tumor Cells - Chromosomal and Molecular Genetic Aberrations of Tumor Cells. - Chichester, UK : John Wiley & Sons, Ltd. - 9781118795538 - 9781118795569 ; , s. 497-514
-
Book chapter (peer-reviewed)abstract
- Cytogenetic information is available on roughly 600 neoplasms originating from the thyroid, parathyroid, pituitary, and adrenal glands; from the thymus; and from the endocrine pancreas. Trisomy 7 is found in 30% of adenomas with clonal cytogenetic aberrations. In both the benign and malignant tumors, a combination of gains of or from chromosomes 5, 7, 12, 17, 19, and 20 was observed. Almost all pituitary tumors arise from the adenohypophysis and are benign adenomas; carcinomas are very rare. The clinical heterogeneity of Neuroblastoma (NB) is well reflected by its cytogenetic and genomic features. Clonal chromosome abnormalities were reported in adrenocortical adenomas. Chromosome banding studies have detected cytogenetic aberrations in adrenocortical carcinomas. Clonal chromosome abnormalities have been reported in several thymomas, usually as part of near-diploid karyotypes as well as in a few thymic carcinomas. The use of comparative genomic hybridization (CGH)-based techniques may improve thymoma subtyping.
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| 21. |
- Calcagnile, O., et al.
(author)
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Telomere dysfunction and telomerase activation in cancer - a pathological paradox?
- 2007
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In: Cytogenetic and Genome Research. - : S. Karger AG. - 1424-859X .- 1424-8581. ; 118:2-4, s. 270-276
-
Journal article (peer-reviewed)abstract
- Telomerase is expressed in more than 90% of human cancers. Telomere maintenance by this enzyme is believed to safeguard genomic integrity in neoplastic cells. Nevertheless, many telomerase-expressing tumours exhibit chromosomal instability triggered by short, dysfunctional telomeres, implying that active telomerase is not sufficient for preserving a functional telosomic nucleoprotein complex in cancer cells. We here examine three possible solutions to this ostensible paradox. First, prior to telomerase activation, telomere erosion may have evolved to a level where telomeric repeat sequences are too short to provide a functional substrate for telomerase enzyme activity. Second, mechanisms other than the continuous telomere erosion counteracted by telomerase may contribute to rapid shortening of telomere repeats. Third, dysfunction of telomere-regulating proteins may result in direct telomere uncapping. Moreover, telomerase may contribute to tumour development also through mechanisms unrelated to telomere length maintenance. Taken together, the available data on the role of telomerase in cancer strongly support that inhibition of this enzyme is a feasible strategy for cancer therapy. Copyright (C) 2007 S. Karger AG, Basel.
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| 22. |
- Chagtai, Tasnim, et al.
(author)
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Gain of 1q as a prognostic biomarker in Wilms Tumors (WTs) treated with preoperative chemotherapy in the International Society of Paediatric Oncology (SIOP) WT 2001 trial : A SIOP renal tumours biology consortium study
- 2016
-
In: Journal of Clinical Oncology. - 0732-183X. ; 34:26, s. 3195-3203
-
Journal article (peer-reviewed)abstract
- Purpose: Wilms tumor (WT) is the most common pediatric renal tumor. Treatment planning under International Society of Paediatric Oncology (SIOP) protocols is based on staging and histologic assessment of response to preoperative chemotherapy. Despite high overall survival (OS), many relapses occur in patients without specific risk factors, and many successfully treated patients are exposed to treatments with significant risks of late effects. To investigate whether molecular biomarkers could improve risk stratification, we assessed 1q status and other potential copy number biomarkers in a large WT series. Materials and Methods: WT nephrectomy samples from 586 SIOP WT 2001 patients were analyzed using a multiplex ligation-dependent probe amplification (MLPA) assay that measured the copy number of 1q and other regions of interest. Results: One hundred sixty-seven (28%) of 586 WTs had 1q gain. Five-year event-free survival (EFS) was 75.0% in patients with 1q gain (95% CI, 68.5% to 82.0%) and 88.2% in patients without gain (95% CI, 85.0% to 91.4%). OS was 88.4% with gain (95% CI, 83.5% to 93.6%) and 94.4% without gain (95% CI, 92.1% to 96.7%). In univariable analysis, 1q gain was associated with poorer EFS (P < .001; hazard ratio, 2.33) and OS (P = .01; hazard ratio, 2.16). The association of 1q gain with poorer EFS retained significance in multivariable analysis adjusted for 1p and 16q loss, sex, stage, age, and histologic risk group. Gain of 1q remained associated with poorer EFS in tumor subsets limited to either intermediate-risk localized disease or nonanaplastic localized disease. Other notable aberrations associated with poorer EFS included MYCN gain and TP53 loss. Conclusion: Gain of 1q is a potentially valuable prognostic biomarker in WT, in addition to histologic response to preoperative chemotherapy and tumor stage.
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| 23. |
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| 24. |
- Chattopadhyay, Subhayan, et al.
(author)
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Tracing the evolution of aneuploid cancers by multiregional sequencing with CRUST
- 2021
-
In: Briefings in Bioinformatics. - : Oxford University Press (OUP). - 1477-4054 .- 1467-5463. ; 22:6
-
Journal article (peer-reviewed)abstract
- Clonal deconvolution of mutational landscapes is crucial to understand the evolutionary dynamics of cancer. Two limiting factors for clonal deconvolution that have remained unresolved are variation in purity and chromosomal copy number across different samples of the same tumor. We developed a semi-supervised algorithm that tracks variant calls through multi-sample spatiotemporal tumor data. While normalizing allele frequencies based on purity, it also adjusts for copy number changes at clonal deconvolution. Absent à priori copy number data, it renders in silico copy number estimations from bulk sequences. Using published and simulated tumor sequences, we reliably segregated clonal/subclonal variants even at a low sequencing depth (~50×). Given at least one pure tumor sample (>70% purity), we could normalize and deconvolve paired samples down to a purity of 40%. This renders a reliable clonal reconstruction well adapted to multi-regionally sampled solid tumors, which are often aneuploid and contaminated by non-cancer cells.
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| 25. |
- Chattopadhyay, Subhayan, et al.
(author)
-
Weaponized genomics : potential threats to international and human security
- 2024
-
In: Nature reviews genetics. - 1471-0056 .- 1471-0064. ; 25:1-2
-
Journal article (peer-reviewed)abstract
- Genetic technologies are revolutionizing human health. In parallel, geopolitical instability has prompted renewed discussions on the risks of DNA technology being weaponized in international conflict. With today’s changing security environment, we argue that risk assessments must be broadened from genetically targeted weapons to a series of new domains.
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| 26. |
- Chen, Dongfeng, et al.
(author)
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Better Prognosis of Patients with Glioma Expressing FGF2-Dependent PDGFRA Irrespective of Morphological Diagnosis.
- 2013
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:4
-
Journal article (peer-reviewed)abstract
- Signaling of platelet derived growth factor receptor alpha (PDGFRA) is critically involved in the development of gliomas. However, the clinical relevance of PDGFRA expression in glioma subtypes and the mechanisms of PDGFRA expression in gliomas have been controversial. Under the supervision of morphological diagnosis, analysis of the GSE16011 and the Repository of Molecular Brain Neoplasia Data (Rembrandt) set revealed enriched PDGFRA expression in low-grade gliomas. However, gliomas with the top 25% of PDGFRA expression levels contained nearly all morphological subtypes, which was associated with frequent IDH1 mutation, 1p LOH, 19q LOH, less EGFR amplification, younger age at disease onset and better survival compared to those gliomas with lower levels of PDGFRA expression. SNP analysis in Rembrandt data set and FISH analysis in eleven low passage glioma cell lines showed infrequent amplification of PDGFRA. Using in vitro culture of these low passage glioma cells, we tested the hypothesis of gliogenic factor dependent expression of PDGFRA in glioma cells. Fibroblast growth factor 2 (FGF2) was able to maintain PDGFRA expression in glioma cells. FGF2 also induced PDGFRA expression in glioma cells with low or non-detectable PDGFRA expression. FGF2-dependent maintenance of PDGFRA expression was concordant with the maintenance of a subset of gliogenic genes and higher rates of cell proliferation. Further, concordant expression patterns of FGF2 and PDGFRA were detected in glioma samples by immunohistochemical staining. Our findings suggest a role of FGF2 in regulating PDGFRA expression in the subset of gliomas with younger age at disease onset and longer patient survival regardless of their morphological diagnosis.
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| 27. |
- Chen, Yin Huai, et al.
(author)
-
Absence of GP130 cytokine receptor signaling causes extended Stüve-Wiedemann syndrome
- 2020
-
In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 217:3
-
Journal article (peer-reviewed)abstract
- The gene IL6ST encodes GP130, the common signal transducer of the IL-6 cytokine family consisting of 10 cytokines. Previous studies have identified cytokine-selective IL6ST defects that preserve LIF signaling. We describe three unrelated families with at least five affected individuals who presented with lethal Stüve-Wiedemann-like syndrome characterized by skeletal dysplasia and neonatal lung dysfunction with additional features such as congenital thrombocytopenia, eczematoid dermatitis, renal abnormalities, and defective acute-phase response. We identified essential loss-of-function variants in IL6ST (a homozygous nonsense variant and a homozygous intronic splice variant with exon skipping). Functional tests showed absent cellular responses to GP130-dependent cytokines including IL-6, IL-11, IL-27, oncostatin M (OSM), and leukemia inhibitory factor (LIF). Genetic reconstitution of GP130 by lentiviral transduction in patient-derived cells reversed the signaling defect. This study identifies a new genetic syndrome caused by the complete lack of signaling of a whole family of GP130-dependent cytokines in humans and highlights the importance of the LIF signaling pathway in pre- and perinatal development.
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| 28. |
- Davidsson, Josef, et al.
(author)
-
Array-based genotype-phenotype correlation in a case of supernumerary ring chromosome 12
- 2008
-
In: Clinical Genetics. - : Wiley. - 0009-9163. ; 73:1, s. 44-49
-
Journal article (peer-reviewed)abstract
- Supernumerary ring chromosomes (SRC) account for approximately 10% of prenatal marker chromosomes and 60% of these SRCs are associated with an abnormal phenotype of the patient carrying them. SRCs have, with few exceptions, not been characterized at the molecular genetic level. Here, we present the first case of a SRC 12 thoroughly investigated with tiling resolution array-based comparative genomic hybridization (array CGH); multicolor, centromere, subtelomeric and whole chromosome painting fluorescence in situ hybridization. In addition, to be able to correlate phenotypic manifestations with a possible pathogenetic outcome of the SRC 12, we retrospectively compared and reviewed all 14 cases of SRC 12 reported, including our present case. Our analyses revealed that the SRC comprised 25.53-46.40 Mb of chromosome 12, a region known to harbor 47 annotated genes of which nine were of putative pathogenetic relevance. Reviewing the previously described cases of SRC 12, we could not establish any specific recurrent features associated with this type of SRC. This most probably reflects heterogeneity in break-point distribution among the reported cases, resulting in differently sized ring chromosomes and hence varying phenotypic traits of the patients. Detailed genomic evaluation, by array CGH or similar techniques may thus be of importance to predict the clinical course in individual cases.
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| 29. |
- Edsjö, Anders, et al.
(author)
-
Building a precision medicine infrastructure at a national level : The Swedish experience
- 2023
-
In: Cambridge Prisms: Precision Medicine. - : Cambridge University Press. - 2752-6143. ; 1
-
Research review (peer-reviewed)abstract
- Precision medicine has the potential to transform healthcare by moving from one-size-fits-all to personalised treatment and care. This transition has been greatly facilitated through new high-throughput sequencing technologies that can provide the unique molecular profile of each individual patient, along with the rapid development of targeted therapies directed to the Achilles heels of each disease. To implement precision medicine approaches in healthcare, many countries have adopted national strategies and initiated genomic/precision medicine initiatives to provide equal access to all citizens. In other countries, such as Sweden, this has proven more difficult due to regionally organised healthcare. Using a bottom-up approach, key stakeholders from academia, healthcare, industry and patient organisations joined forces and formed Genomic Medicine Sweden (GMS), a national infrastructure for the implementation of precision medicine across the country. To achieve this, Genomic Medicine Centres have been established to provide regionally distributed genomic services, and a national informatics infrastructure has been built to allow secure data handling and sharing. GMS has a broad scope focusing on rare diseases, cancer, pharmacogenomics, infectious diseases and complex diseases, while also providing expertise in informatics, ethical and legal issues, health economy, industry collaboration and education. In this review, we summarise our experience in building a national infrastructure for precision medicine. We also provide key examples how precision medicine already has been successfully implemented within our focus areas. Finally, we bring up challenges and opportunities associated with precision medicine implementation, the importance of international collaboration, as well as the future perspective in the field of precision medicine.
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| 30. |
- Edsjö, Anders, et al.
(author)
-
Current and emerging sequencing-based tools for precision cancer medicine
- 2024
-
In: Molecular Aspects of Medicine. - 0098-2997 .- 1872-9452. ; 96
-
Research review (peer-reviewed)abstract
- Current precision cancer medicine is dependent on the analyses of a plethora of clinically relevant genomic aberrations. During the last decade, next-generation sequencing (NGS) has gradually replaced most other methods for precision cancer diagnostics, spanning from targeted tumor-informed assays and gene panel sequencing to global whole-genome and whole-transcriptome sequencing analyses. The shift has been impelled by a clinical need to assess an increasing number of genomic alterations with diagnostic, prognostic and predictive impact, including more complex biomarkers (e.g. microsatellite instability, MSI, and homologous recombination deficiency, HRD), driven by the parallel development of novel targeted therapies and enabled by the rapid reduction in sequencing costs. This review focuses on these sequencing-based methods, puts their emergence in a historic perspective, highlights their clinical utility in diagnostics and decision-making in pediatric and adult cancer, as well as raises challenges for their clinical implementation. Finally, the importance of applying sensitive tools for longitudinal monitoring of treatment response and detection of measurable residual disease, as well as future avenues in the rapidly evolving field of sequencing-based methods are discussed.
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| 31. |
- Ehinger, Daniel, et al.
(author)
-
SIX1 as a Novel Immunohistochemical Marker in the Differential Diagnosis of Rhabdomyosarcoma
- 2023
-
In: Fetal and Pediatric Pathology. - 1551-3815. ; 42:5, s. 723-734
-
Journal article (peer-reviewed)abstract
- Background: Differential diagnosis of rhabdomyosarcoma (RMS) is challenging. Sineoculis homeobox homolog 1 (SIX1) is an oncogene involved in skeletal muscle differentiation. We compared protein expression patterns of SIX1 in RMS and its most common differential diagnoses. Methods: SIX1 immunohistochemistry in 36 RMS and in 33 tumors from seven differential diagnostic subtypes were evaluated. The fraction of SIX1 positive tumor cells was scored by three independent observers. Results: A majority (75%) of the evaluated RMS expressed SIX1 in at least 50% of tumor cells and all except one RMS had more than 25% positive tumor cells. Neuroblastoma had less than 1% SIX1 positive tumor cells. Gonadoblastoma, malignant rhabdoid tumor, and Ewing sarcoma had 10% or less positive tumor cells. Pleuropulmonary blastoma exhibited 26–50% positive tumor cells and synovial sarcoma >50% positive cells. Conclusion: SIX1 immunohistochemistry is positive in most RMS, and occasionally in some tumors within the differential diagnoses of RMS.
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| 32. |
- Ellaithi, Mona, et al.
(author)
-
A case of Cornelia de Lange syndrome from Sudan
- 2007
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In: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 7
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Brachmann de Lange syndrome (BDLS) is a multiple congenital anomaly syndrome characterized by a distinctive facial appearance, prenatal and postnatal growth deficiency, psychomotor delay, behavioral problems, and malformations of the upper extremities. CASE PRESENTATION: Here we present for the first time a case of BDLS from Sudan, a 7-month-old female infant, who was referred as a case of malnutrition. The patient was from a Sudanese western tribe. Clinical investigation showed that the child was a classical case of BDLS, but with some additional clinical findings not previously reported including crowded ribs and tied tongue. CONCLUSION: Reporting BDLS cases of different ethnic backgrounds could add nuances to the phenotypic description of the syndrome and be helpful in diagnosis.
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| 33. |
- Ellaithi, M, et al.
(author)
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A del(X)(p11) carrying SRY sequences in an infant with ambiguous genitalia
- 2006
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In: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 6:11
-
Journal article (peer-reviewed)abstract
- BACKGROUND: SRY (sex-determining region, Y) is the gene responsible of gonadal differentiation in the male and it is essential for the regular development of male genitalia. Translocations involving the human sex chromosomes are rarely reported, however here we are reporting a very rare translocation of SRY gene to the q -arm of a deleted X chromosome. This finding was confirmed by cytogenetic, fluorescent in situ hybridization (FISH) and polymerase chain reaction (PCR). CASE PRESENTATION: A 7-month infant was clinically diagnosed as an intersex case, with a phallus, labia majora and minora, a blind vagina and a male urethra. Neither uterus nor testes was detected by Ultrasonography. G-banding of his chromosomes showed 46,X,del(X)(p11) and fluorescent in situ hybridization (FISH) analysis showed a very small piece from the Y chromosome translocated to the q-arm of the del(X). Polymerase chain reaction (PCR) analysis revealed the presence of material from the sex-determining region Y (SRY) gene. CONCLUSION: It is suggested that the phenotype of the patient was caused by activation of the deleted X chromosome with SRY translocation, which is responsible for gonadal differentiation.
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| 34. |
- Ellaithi, M, et al.
(author)
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Female genital mutilation of a karyotypic male presenting as a female with delayed puberty
- 2006
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In: BMC Women's Health. - : Springer Science and Business Media LLC. - 1472-6874. ; 6:6
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Female genital mutilation (FGM) is commonly practiced mainly in a belt reaching from East to West Africa north of the equator. The practice is known across socio-economic classes and among different ethnic, religious, and cultural groups. Few studies have been appropriately designed to measure the health effects of FGM. However, the outcome of FGM on intersex individuals has never been discussed before. CASE PRESENTATION: The patient first presented as a female with delayed puberty. Hormonal analysis revealed a normal serum prolactin level of 215 Micro/L, a low FSH of 0.5 Micro/L, and a low LH of 1.1 Micro/L. Type IV FGM (Pharaonic circumcision) had been performed during childhood. Chromosomal analysis showed a 46, XY karyotype and ultrasonography verified a soft tissue structure in the position of the prostate. CONCLUSION: FGM pose a threat to the diagnosis and management of children with abnormal genital development in the Sudan and similar societies.
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| 35. |
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| 36. |
- Forsberg, Lars A., et al.
(author)
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Mosaicism in health and disease — clones picking up speed
- 2017
-
In: Nature reviews genetics. - : Springer Science and Business Media LLC. - 1471-0056 .- 1471-0064. ; 18:2, s. 128-142
-
Research review (peer-reviewed)abstract
- Post-zygotic variation refers to genetic changes that arise in the soma of an individual and that are not usually inherited by the next generation. Although there is a paucity of research on such variation, emerging studies show that it is common: individuals are complex mosaics of genetically distinct cells, to such an extent that no two somatic cells are likely to have the exact same genome. Although most types of mutation can be involved in post-zygotic variation, structural genetic variants are likely to leave the largest genomic footprint. Somatic variation has diverse physiological roles and pathological consequences, particularly when acquired variants influence the clonal trajectories of the affected cells. Post-zygotic variation is an important confounder in medical genetic testing and a promising avenue for research: future studies could involve analyses of sorted and single cells from multiple tissue types to fully explore its potential.
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| 37. |
- Forslund, Ola, et al.
(author)
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Regarding human cytomegalovirus in neuroblastoma.
- 2014
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In: Cancer Medicine. - : Wiley. - 2045-7634. ; 3:4, s. 1038-1040
-
Journal article (other academic/artistic)abstract
- Wolmer-Solberg et al., reported that six human neuroblastoma cell lines and the vast majority of clinical neuroblastoma samples contained HCMV DNA and expressed HCMV proteins. We could not replicate the data and therefore remain skeptical towards the prevalence of HCMV DNA in neuroblastomas.
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| 38. |
- Fransson, Emma, et al.
(author)
-
Diagnostic Efficacy of Rectal Suction Biopsy with Regard to Weight in Children Investigated for Hirschsprung's Disease
- 2022
-
In: Children. - : MDPI AG. - 2227-9067. ; 9:2, s. 1-9
-
Journal article (peer-reviewed)abstract
- BACKGROUND/AIM: Diagnostic efficacy, defined as the percentage of rectal suction biopsy (RSB) specimens sufficient enough to determine the absence of ganglia cells in Hirschsprung's disease (HD) diagnosis, has been reported to be low, requiring repeated biopsies. The aim was to explore whether RSB diagnostic efficacy was influenced by the child's weight and to ascertain whether RSB efficacy differed between aganglionic and ganglionic tissue.MATERIALS AND METHODS: Efficacy analyses were conducted in a national HD-center's register on children 0-15 kg, examined between 2011-2019. First-time RSB diagnostic efficacy was correlated to the children's weight and final HD diagnosis.RESULTS: Among the 84 children who had first-time RSB, the overall diagnostic efficacy was 85% (71/84). The efficacy was higher among children weighing less than the identified cut-off of 9.0 kg (89% in 0-9.0 kg versus 62% in 9.01-15.0 kg, p = 0.026). Among children diagnosed with HD, 96% (26/27) weighed 0-9.0 kg. In this weight group, the diagnostic efficacy was lower in aganglionosis compared to ganglionosis (77%; 20/26 versus 96%; 43/45), p = 0.045).CONCLUSIONS: The RSB diagnostic efficacy was significantly higher in children weighing less than 9.0 kg and was less in aganglionic compared to ganglionic tissue. Therefore, weight can be useful to predict RSB diagnostic efficacy.
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| 39. |
- Fransson, Emma, et al.
(author)
-
Systematic orientation of fresh rectal suction biopsies improves histopathological diagnostics in hirschsprung’s disease – a method description and preliminary report
- 2023
-
In: BMC Pediatrics. - 1471-2431. ; 23
-
Journal article (peer-reviewed)abstract
- Background: Optimizing rectal suction biopsy (RSB) diagnostics in Hirschsprung’s disease (HD) may shorten diagnostic time and prevent need for repeated biopsies. Aim: To explore whether systematic orientation of fresh RSB specimens increased biopsy quality, diagnostic times, diagnostic efficacy, and histopathologic workload, and to explore these outcome measures for aganglionic specimens. Materials/Methods: This was an observational case-control study conducted at a national referral center for HD on data collected from the local HD-diagnostic register. From 2019 each fresh RSB was oriented by the collector in a notch in a foam cushion, placed in a separate cassette, and sent in formalin for pathological analysis. Outcome measures of oriented RSB samples collected 2019–2021 were compared to those of non-oriented RSB samples collected 2015–2018. Staining/immunohistochemistry consisted of hematoxylin eosin, S-100 and calretinin. Results: 78 children with 81 RSBs and 242 biopsy analyzes were included. The frequency of high-quality RSB specimens was higher in oriented: 40% (42/106) versus non-oriented 25% (34/136) (p = 0.018), the diagnostic turnaround time was shorter: 2 days (1–5) versus 3 days (2–8) (p = 0.015), and the number of additional sectioning/leveling/re-orientation per biopsy was lower: 7 (3–26) versus 16 (7–72) (p = 0.011). Specifically for aganglionic specimens, the frequency of high-quality biopsies was generally higher in oriented than in non-oriented RSB specimens: 47% (28/59) versus 14% (7/50) (p < 0.001); the diagnostic efficacy was higher 95% (19/20) versus 60% (9/15) (p = 0.027) and the diagnostic turnaround time shorter: 2 days (2–3) versus 3 days (2–8) (p = 0.036). Conclusions: Systematic orientation of fresh RSB specimens improves HD diagnostics. Improvement was consistent in aganglionic specimens.
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| 40. |
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| 41. |
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| 42. |
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| 43. |
- Gisselsson, David, et al.
(author)
-
Cancer : An Insurgency of Clones
- 2017
-
In: Trends in cancer. - : Elsevier BV. - 2405-8025 .- 2405-8033. ; 3:2, s. 73-75
-
Journal article (other academic/artistic)abstract
- Oncological therapy resembles a military force that eliminates the central power of a country (dominant clone of a cancer) to create a vacuum where insurgents (subclones) thrive and instigate rebellion (relapse). We suggest that military counterinsurgency doctrine can inspire a discussion of cancer that uniquely embraces both cancer cell evolution and tumour microenvironment.
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| 44. |
- Gisselsson, David, et al.
(author)
-
Clonal evolution through genetic bottlenecks and telomere attrition : Potential threats to in vitro data reproducibility
- 2019
-
In: Genes Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 58:7, s. 452-461
-
Research review (peer-reviewed)abstract
- Tissue cultures of immortalized human cells, also known as established cell lines, are broadly accessible and cost-efficient tools for biomedical research. We here review potential genetic sources of systematic error in cell line experiments due to clonal evolution in vitro. In particular, the authors highlight alterations in telomere function over prolonged culture and population bottlenecks, respectively, as two commonly overlooked phenomena that can result in significant alterations in cell line genotypes over just one or a few passages in vitro. These alterations may include changes in mutation status of oncogenes and large scale chromosomal imbalances. We introduce a simple list of factors to be avoided in order to reduce the risk of data misinterpretation due to clonal evolution, including unacknowledged in vitro selection pressures, prolonged culture per se, harsh population size reductions, experiments at early phases after establishment, and the employment of cell lines not sufficiently analyzed by high resolution genetic techniques.
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| 45. |
- Gisselsson, David, et al.
(author)
-
Cytogenetic methods
- 2015. - 4th
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In: Cancer Cytogenetics : Chromosomal and Molecular Genetic Aberrations of Tumor Cells - Chromosomal and Molecular Genetic Aberrations of Tumor Cells. - Chichester, UK : John Wiley & Sons, Ltd. - 9781118795538 - 9781118795569 ; , s. 11-18
-
Book chapter (peer-reviewed)abstract
- This chapter outlines the methods currently employed in cancer cytogenetics, spanning from chromosome banding to array- and sequencing-based techniques. A correct sampling procedure is the basis for correct scientific and diagnostic conclusions. Chromosome preparation requires live cells, whereas in situ hybridization at least requires intact nuclei, and genome arrays as well as sequencing rely on DNA that has not been extensively degraded. Direct preparations or short-term cultures are therefore usually preferred for chromosome banding analysis. In situ hybridization techniques are based on the inherent organization of DNA into two antiparallel complementary strands. Genomic arrays are highly efficient tools for obtaining data on genomic imbalances present in a tumor sample. The advent of massive parallel/second-generation/ next-generation sequencing (NGS technology has radically transformed the field of cancer cytogenetics. More than 800 genomes of more than 25 cancer types have now been sequenced.
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| 46. |
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| 47. |
- Gisselsson Nord, David
(author)
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Aneuploidy in cancer: Sudden or sequential?
- 2011
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In: Cell Cycle. - : Informa UK Limited. - 1551-4005 .- 1538-4101. ; 10:3, s. 359-361
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Journal article (peer-reviewed)abstract
- Comment on: Gisselsson D, et al. Proc Natl Acad Sci USA 2010; 107:20489-93.
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| 48. |
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| 49. |
- Gisselsson Nord, David, et al.
(author)
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Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity
- 2000
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In: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 97:10, s. 5357-5362
-
Journal article (peer-reviewed)abstract
- It has long been known that rearrangements of chromosomes through breakage-fusion-bridge (BFB) cycles may cause variability of phenotypic and genetic traits within a cell population. Because intercellular heterogeneity is often found in neoplastic tissues, we investigated the occurrence of BFB events in human solid tumors. Evidence of frequent BFB events was found in malignancies that showed unspecific chromosome aberrations, including ring chromosomes, dicentric chromosomes, and telomeric associations, as well as extensive intratumor heterogeneity in the pattern of structural changes but not in tumors with tumor-specific aberrations and low variability. Fluorescence in situ hybridization analysis demonstrated that chromosomes participating in anaphase bridge formation were involved in a significantly higher number of structural aberrations than other chromosomes. Tumors with BFB events showed a decreased elimination rate of unstable chromosome aberrations after irradiation compared with normal cells and other tumor cells. This result suggests that a combination of mitotically unstable chromosomes and an elevated tolerance to chromosomal damage leads to constant genomic reorganization in many malignancies, thereby providing a flexible genetic system for clonal evolution and progression.
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| 50. |
- Gisselsson Nord, David
(author)
-
Chromosomal Instability and Genomic Amplification in Bone and Soft Tissue Tumours
- 2000
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Doctoral thesis (other academic/artistic)abstract
- Acquired genetic abnormalities are found in all types of malignant tumours and may contribute to neoplastic processes by altering protein structure or dosage. Many bone and soft tissue tumours (BSTT) are characterised by complex patterns of chromosome changes, including extensive intratumour heterogeneity and amplification of DNA sequences. The results presented in this thesis demonstrate that the cytogenetic heterogeneity in a number of BSTT may, to a considerable extent, be caused by ring and dicentric chromosomes involved in breakage-fusion-bridge (BFB) events, as shown by the strong correlation between sequences present in mitotically unstable chromosomes and anaphase bridges. In borderline/low-malignant tumours with ring chromosomes carrying amplified sequences from chromosome 12, BFB rearrangements are associated with intratumour variability in the organisation of amplified material and abnormalities in centromeric alpha satellite sequences, including neocentromere formation. After the healing of broken ends by telomeric sequences from other chromosomes, rings may transform into giant marker chromosomes, which may occasionally be dicentric and rearrange further. BFB instability is also present in highly malignant tumours exhibiting a complex, unspecific, and heterogeneous pattern of chromosome aberrations. These neoplasms typically show unstable dicentric chromosomes and a general destabilisation of the chromosome complement. Tumour cells with BFB instability exhibit a decreased elimination rate of mitotically unstable chromosomes, which may be partly related to disruption of the normal TP53–dependent DNA damage response. In both BSTT and epithelial tumours, BFB events are associated with specific abnormalities in nuclear shape, indicating that nuclear atypia may serve as an indicator of ongoing genomic reorganisation in neoplastic cell populations.
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