648 results on '"Gisselsson, David"'
Search Results
202. Characterization of chromosome aberrations in salivary gland tumors by FISH, including multicolor COBRA-FISH
- Author
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Jin, Charlotte, primary, Martins, Carmo, additional, Jin, Yuesheng, additional, Wiegant, Joop, additional, Wennerberg, Johan, additional, Dictor, Michael, additional, Gisselsson, David, additional, Strömbeck, Bodil, additional, Fonseca, Isabel, additional, Mitelman, Felix, additional, Tanke, Hans J., additional, Höglund, Mattias, additional, and Mertens, Fredrik, additional
- Published
- 2001
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203. Abnormal Nuclear Shape in Solid Tumors Reflects Mitotic Instability
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Gisselsson, David, primary, Björk, Jonas, additional, Höglund, Mattias, additional, Mertens, Fredrik, additional, Dal Cin, Paola, additional, Åkerman, Måns, additional, and Mandahl, Nils, additional
- Published
- 2001
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204. Unique Cytologic and Chromosome Aberrations in Chondroid Lipoma
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Domanski, Henryk A., primary, Gisselsson, David, additional, Mertens, Fredrik, additional, and Mandahl, Nils, additional
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- 2000
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205. Chromosomal breakage-fusion-bridge events cause genetic intratumor heterogeneity
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Gisselsson, David, primary, Pettersson, Louise, additional, Höglund, Mattias, additional, Heidenblad, Markus, additional, Gorunova, Ludmila, additional, Wiegant, Joop, additional, Mertens, Fredrik, additional, Dal Cin, Paola, additional, Mitelman, Felix, additional, and Mandahl, Nils, additional
- Published
- 2000
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206. Cytogenetics of hepatoblastoma: Further characterization of 1q rearrangements by fluorescence in situ hybridization: An international collaborative study
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Parada, Luis Antonio, primary, Limon, Janusz, additional, Iliszko, Mariola, additional, Czauderna, Piotr, additional, Gisselsson, David, additional, H�glund, Mattias, additional, Kullendorff, Carl-Magnus, additional, Wiebe, Thomas, additional, Mertens, Fredrik, additional, and Johansson, Bertil, additional
- Published
- 2000
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207. Locus-specific multifluor FISH analysis allows physical characterization of complex chromosome abnormalities in neoplasia
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Gisselsson, David, primary, Mandahl, Nils, additional, P�lsson, Eva, additional, Gorunova, Ludmila, additional, and H�glund, Mattias, additional
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- 2000
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208. Whole chromosome gain does not in itself confer cancer-like chromosomal instability.
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Valind, Anders, Jin, Yuesheng, Baldetorp, Bo, and Gisselsson, David
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CANCER patients ,MOSAICISM ,CELL nuclei ,CHROMOSOMES ,TRISOMY - Abstract
Constitutional aneuploidy is typically caused by a single-event meiotic or early mitotic error. In contrast, somatic aneuploidy, found mainly in neoplastic tissue, is attributed to continuous chromosomal instability. More debated as a cause of aneuploidy is aneuploidy itself; that is, whether aneuploidy per se causes chromosomal instability, for example, in patients with inborn aneuploidy. We have addressed this issue by quantifying the level of somatic mosaicism, a proxy marker of chromosomal instability, in patients with constitutional aneuploidy by precise background-filtered dual-color FISH. In contrast to previous studies that used less precise methods, we find that constitutional trisomy, even for large chromosomes that are often trisomic in cancer, does not confer a significantly elevated rate of somatic chromosomal mosaicism in individual cases. Constitutional triploidy was associated with an increased level of somatic mosaicism, but this consisted mostly of reversion from trisomy to disomy and did not correspond to a proportionally elevated level of chromosome mis-segregation in triploids, indicating that the observed mosaicism resulted from a specific accumulation of cells with a hypotriploid chromosome number. In no case did the rate of somatic mosaicism in constitutional aneuploidy exceed that of "chromosomally stable" cancer cells. Our findings show that even though constitutional aneuploidy was in some cases associated with low-level somatic mosaicism, it was insufficient to generate the cancer-like levels expected if aneuploidy single-handedly triggered cancer-like chromosomal instability. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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209. Unique Cytological Features and Chromosome Aberrations in Chondroid Lipoma
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Gisselsson, David, primary, Domanski, Henryk A., additional, Höglund, Mattias, additional, Carlén, Birgitta, additional, Mertens, Fredrik, additional, Willén, Helena, additional, and Mandahl, Nils, additional
- Published
- 1999
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210. Hibernomas are Characterized by Homozygous Deletions in the Multiple Endocrine Neoplasia Type I Region
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Gisselsson, David, primary, Höglund, Mattias, additional, Mertens, Fredrik, additional, Dal Cin, Paola, additional, and Mandahl, Nils, additional
- Published
- 1999
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211. Amplification of 12q13 and 12q15 Sequences in a Sclerosing Epithelioid Fibrosarcoma
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Gisselsson, David, primary, Andreasson, Patrik, additional, Meis-Kindblom, Jeanne M., additional, Kindblom, Lars-Gunnar, additional, Mertens, Fredrik, additional, and Mandahl, Nils, additional
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- 1998
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212. A case of dermatofibrosarcoma protuberans with a ring chromosome 5 and a rearranged chromosome 22 containing amplified COL1A1 and PDGFB sequences
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Gisselsson, David, primary, Höglund, Mattias, additional, O’Brien, Kevin P., additional, Dumanski, Jan P., additional, Mertens, Fredrik, additional, and Mandahl, Nils, additional
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- 1998
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213. Chromosomal organization of amplified chromosome 12 sequences in mesenchymal tumors detected by fluorescence in situ hybridization
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Gisselsson, David, primary, Höglund, Mattias, additional, Mertens, Fredrik, additional, Mitelman, Felix, additional, and Mandahl, Nils, additional
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- 1998
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214. Gene fusion detection in formalin-fixed paraffin-embedded benign fibrous histiocytomas using fluorescence in situ hybridization and RNA sequencing.
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Walther, Charles, Hofvander, Jakob, Nilsson, Jenny, Magnusson, Linda, Domanski, Henryk A, Gisselsson, David, Tayebwa, Johnbosco, Doyle, Leona A, Fletcher, Christopher DM, and Mertens, Fredrik
- Published
- 2015
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215. Elevated Tolerance to Aneuploidy in Cancer Cells: Estimating the Fitness Effects of Chromosome Number Alterations by In Silico Modelling of Somatic Genome Evolution.
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Valind, Anders, Jin, Yuesheng, and Gisselsson, David
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ANEUPLOIDY ,CANCER cells ,PLOIDY ,GENOMES ,CHROMOSOME abnormalities ,CANCER genetics ,HUMAN genetics - Abstract
An unbalanced chromosome number (aneuploidy) is present in most malignant tumours and has been attributed to mitotic mis-segregation of chromosomes. However, recent studies have shown a relatively high rate of chromosomal mis-segregation also in non-neoplastic human cells, while the frequency of aneuploid cells remains low throughout life in most normal tissues. This implies that newly formed aneuploid cells are subject to negative selection in healthy tissues and that attenuation of this selection could contribute to aneuploidy in cancer. To test this, we modelled cellular growth as discrete time branching processes, during which chromosome gains and losses were generated and their host cells subjected to selection pressures of various magnitudes. We then assessed experimentally the frequency of chromosomal mis-segregation as well as the prevalence of aneuploid cells in human non-neoplastic cells and in cancer cells. Integrating these data into our models allowed estimation of the fitness reduction resulting from a single chromosome copy number change to an average of ≈30% in normal cells. In comparison, cancer cells showed an average fitness reduction of only 6% (p = 0.0008), indicative of aneuploidy tolerance. Simulations based on the combined presence of chromosomal mis-segregation and aneuploidy tolerance reproduced distributions of chromosome aberrations in >400 cancer cases with higher fidelity than models based on chromosomal mis-segregation alone. Reverse engineering of aneuploid cancer cell development in silico predicted that aneuploidy intolerance is a stronger limiting factor for clonal expansion of aneuploid cells than chromosomal mis-segregation rate. In conclusion, our findings indicate that not only an elevated chromosomal mis-segregation rate, but also a generalised tolerance to novel chromosomal imbalances contribute to the genomic landscape of human tumours. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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216. Copy number defects of G1-Cell cycle genes in neuroblastoma are frequent and correlate with high expression of E2F target genes and a poor prognosis.
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Molenaar, Jan J., Koster, Jan, Ebus, Marli E., van Sluis, Peter, Westerhout, Ellen M., de Preter, Katleen, Gisselsson, David, Øra, Ingrid, Speleman, Frank, Caron, Huib N., and Versteeg, Rogier
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- 2012
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217. A First Cytogenetic Study of Down Syndrome in Sudan.
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Ellaithi, Mona, Nilsson, Therese, A, Atif Elagib, Fadl-Elmula, Imad, and Gisselsson, David
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- 2008
218. The immune cell atlas of human neuroblastoma
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Verhoeven, Bronte Manouk, Mei, Shenglin, Olsen, Thale Kristin, Gustafsson, Karin, Valind, Anders, Lindström, Axel, Gisselsson, David, Fard, Shahrzad Shirazi, Hagerling, Catharina, Kharchenko, Peter V., Kogner, Per, Johnsen, John Inge, and Baryawno, Ninib
- Abstract
Understanding the complete immune cell composition of human neuroblastoma (NB) is crucial for the development of immunotherapeutics. Here, we perform single-cell RNA sequencing (scRNA-seq) on 19 human NB samples coupled with multiplex immunohistochemistry, survival analysis, and comparison with normal fetal adrenal gland data. We provide a comprehensive immune cell landscape and characterize cell-state changes from normal tissue to NB. Our analysis reveals 27 immune cell subtypes, including distinct subpopulations of myeloid, NK, B, and T cells. Several different cell types demonstrate a survival benefit. In contrast to adult cancers and previous NB studies, we show an increase in inflammatory monocyte cell state when contrasting normal and tumor tissue, while no differences in cytotoxicity and exhaustion score for T cells, nor in Treg activity, are observed. Our receptor-ligand interaction analysis reveals a highly complex interactive network of the NB microenvironment from which we highlight several interactions that we suggest for future therapeutic studies.
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- 2022
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219. Differentially amplified chromosome 12 sequences in low- and high-grade osteosarcoma.
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Gisselsson, David, Pålsson, Eva, Höglund, Mattias, Domanski, Henryk, Mertens, Fredrik, Pandis, Nikos, Sciot, Raf, Dal Cin, Paola, Bridge, Julia A., and Mandahl, Nils
- Published
- 2002
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220. Cytogenetic aberrations and their prognostic impact in chondrosarcoma.
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Mandahl, Nils, Gustafson, Pelle, Mertens, Fredrik, Åkerman, Måns, Baldetorp, Bo, Gisselsson, David, Knuutila, Sakari, Bauer, Henrik C. F., and Larsson, Olle
- Published
- 2002
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221. Abstracts of Theses from the Nordic Countries.
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Lof, Johan, Danielsson, Rimma, Johansson, Amanda, Gisselsson, David, Skog, Anna-Lena Hjelm, Hongyun Li, Dasu, Alexandru, and Bergenmar, Mia
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CANCER treatment ,RADIOTHERAPY ,NUCLEAR medicine ,HYPOXEMIA - Abstract
Presents several abstracts on cancer treatment in the Nordic countries. Development of a general framework for optimization of radiation therapy; Role of nuclear medicine in diagnosis of breast cancer and regional lymph nodes; Impact of hypoxia on novel radiotherapy.
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- 2001
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222. Building a precision medicine infrastructure at a national level: The Swedish experience.
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Edsjö, Anders, Lindstrand, Anna, Gisselsson, David, Mölling, Paula, Friedman, Mikaela, Cavelier, Lucia, Johansson, Maria, Ehrencrona, Hans, Fagerqvist, Therese, Strid, Tobias, Lovmar, Lovisa, Jacobsson, Bo, Johansson, Åsa, Engstrand, Lars, Wheelock, Craig E., Sikora, Per, Wirta, Valtteri, Fioretos, Thoas, and Rosenquist, Richard
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INDIVIDUALIZED medicine , *COMMUNICABLE diseases , *PHARMACOGENOMICS , *RARE diseases , *GRAND strategy (Political science) , *EXPERTISE - 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 highthroughput 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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223. PLAG1Alterations in Lipoblastoma
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Gisselsson, David, Hibbard, Michele K., Dal Cin, Paola, Sciot, Raf, Hsi, Bae-Li, Kozakewich, Harry P., and Fletcher, Jonathan A.
- Abstract
Lipoblastomas are rare soft tissue tumors that occur primarily in young children. They typically contain variably differentiated adipocytes, primitive mesenchymal cells, myxoid matrix, and fibrous trabeculae. Abnormalities in chromosome 8, leading to rearrangements of the PLAG1gene, were demonstrated recently in four lipoblastomas. In the present report, we determine the frequency of PLAG1alterations in 16 lipoblastomas from children aged 13 years or younger, and we also evaluate the stages of lipoblastoma differentiation at which PLAG1genomic alterations are found. Eleven lipoblastomas (69%), including those with either classic or lipoma-like histology, had rearrangements of the 8q12 PLAG1region. Another three lipoblastomas had polysomy for chromosome 8 in the absence of PLAG1rearrangement. Only two cases (13%) lacked a chromosome 8 abnormality. Notably, the lipoblastomas with chromosome 8 polysomy had up to five copies of chromosome 8 as an isolated cytogenetic finding in an otherwise diploid cell. We also demonstrate that PLAG1alterations are found in a spectrum of mesenchymal cell types in lipoblastomas, including lipoblasts, mature adipocytes, primitive mesenchymal cells, and fibroblast-like cells. This finding is consistent with neoplastic origin in a primitive mesenchymal precursor and with variable differentiation to a mature adipocyte end-point. Hence, our studies provide biological validation for the clinical observation that lipoblastomas can evolve into mature, lipoma-like, lesions. They also suggest that PLAG1dosage alterations caused by polysomy 8 might represent an alternative oncogenic mechanism in lipoblastoma.
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- 2001
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224. Aneuploidy in cancer.
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Gisselsson, David
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- 2011
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225. SIX1 as a Novel Immunohistochemical Marker in the Differential Diagnosis of Rhabdomyosarcoma.
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Ehinger, Daniel, Frostberg, Hanna, Larsson, Sofia, and Gisselsson, David
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SYNOVIOMA , *RHABDOMYOSARCOMA , *DIFFERENTIAL diagnosis , *EWING'S sarcoma , *SKELETAL muscle , *PROTEIN expression - 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. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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226. Macrophage infiltration promotes regrowth in MYCN-amplified neuroblastoma after chemotherapy.
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Valind, Anders, Verhoeven, Bronte Manouk, Enoksson, Jens, Karlsson, Jenny, Christensson, Gustav, Mañas, Adriana, Aaltonen, Kristina, Jansson, Caroline, Bexell, Daniel, Baryawno, Ninib, Gisselsson, David, and Hagerling, Catharina
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NEUROBLASTOMA , *MACROPHAGES , *RNA sequencing , *CANCER chemotherapy , *DISEASE remission , *DISEASE relapse - Abstract
Despite aggressive treatment, the 5-year event-free survival rate for children with high-risk neuroblastoma is <50%. While most high-risk neuroblastoma patients initially respond to treatment, often with complete clinical remission, many eventually relapse with therapy-resistant tumors. Novel therapeutic alternatives that prevent the recurrence of therapy-resistant tumors are urgently needed. To understand the adaptation of neuroblastoma under therapy, we analyzed the transcriptomic landscape in 46 clinical tumor samples collected before (PRE) or after (POST) treatment from 22 neuroblastoma patients. RNA sequencing revealed that many of the top-upregulated biological processes in POST MYCN amplified (MNA+) tumors compared to PRE MNA+ tumors were immune-related, and there was a significant increase in numerous genes associated with macrophages. The infiltration of macrophages was corroborated by immunohistochemistry and spatial digital protein profiling. Moreover, POST MNA+ tumor cells were more immunogenic compared to PRE MNA+ tumor cells. To find support for the macrophage-induced outgrowth of certain subpopulations of immunogenic tumor cells following treatment, we examined the genetic landscape in multiple clinical PRE and POST tumor samples from nine neuroblastoma patients revealing a significant correlation between an increased amount of copy number aberrations (CNA) and macrophage infiltration in POST MNA+ tumor samples. Using an in vivo neuroblastoma patient-derived xenograft (PDX) chemotherapy model, we further show that inhibition of macrophage recruitment with anti-CSF1R treatment prevents the regrowth of MNA+ tumors following chemotherapy. Taken together, our work supports a therapeutic strategy for fighting the relapse of MNA+ neuroblastoma by targeting the immune microenvironment. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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227. DEVOLUTION—A method for phylogenetic reconstruction of aneuploid cancers based on multiregional genotyping data.
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Andersson, Natalie, Chattopadhyay, Subhayan, Valind, Anders, Karlsson, Jenny, and Gisselsson, David
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ANEUPLOIDY , *GENOTYPES , *DATA analysis , *BIOINFORMATICS , *COMPUTER algorithms - 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. Natalie Andersson et al. present DEVOLUTION, an algorithm and tool that allows researchers to reconstruct tumor clonal lineages from copy number and/or sequencing data. They validate this method on a diverse cohort of pediatric cancers, demonstrating its potential applications for cancer research. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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228. Chemotherapy, host response and molecular dynamics in periampullary cancer: the CHAMP study.
- Author
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Hau, Sofie Olsson, Petersson, Alexandra, Nodin, Björn, Karnevi, Emelie, Boman, Karolina, Williamsson, Caroline, Eberhard, Jakob, Leandersson, Karin, Gisselsson, David, Heby, Margareta, and Jirström, Karin
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MOLECULAR dynamics , *THERAPEUTICS , *CANCER chemotherapy , *CANCER , *PANCREATIC cancer , *PANCREATIC tumors , *TISSUE arrays , *RESEARCH , *DNA , *SEQUENCE analysis , *CLINICAL trials , *RESEARCH methodology , *ARTHRITIS Impact Measurement Scales , *ANTINEOPLASTIC agents , *PROGNOSIS , *EVALUATION research , *MEDICAL cooperation , *DUODENUM , *DUCTAL carcinoma , *COMPARATIVE studies , *GENES , *RESEARCH funding , *COMBINED modality therapy , *PALLIATIVE treatment , *LONGITUDINAL method , *PHARMACODYNAMICS - Abstract
Background: Pancreatic cancer is a devastating disease with a dismal prognosis. Despite profound medical advances in systemic therapies for other types of aggressive tumours during recent years, a diagnosis of pancreatic cancer is still often synonymous with a fatal outcome. The term periampullary cancer includes pancreatic cancer and applies to the group of tumours found in proximity to the ampulla of Vater. Molecular events and immune response in the host during chemotherapy remain largely unexplored in this group of tumours. Therefore, the "Chemotherapy, Host Response and Molecular Dynamics in Periampullary Cancer (CHAMP)" study aims to monitor these processes to gain new insight into this perplexing disease.Methods: The CHAMP study is a prospective, single-arm observational study. All patients diagnosed with pancreatic or other periampullary adenocarcinoma undergoing adjuvant or palliative chemotherapy treatment in the Department of Oncology, Skåne University Hospital, are invited to participate. Clinical and pathological data will be compiled at study entry. A single tissue microarray (TMA) block is constructed for each patient with a resected tumour and blood samples are drawn before, during and after chemotherapy in order to sample peripheral blood mononuclear cells (PBMC), cytokines and circulating tumour DNA (ctDNA). Next generation sequencing will be performed on tumour tissue and ctDNA to detect changes in the clonal landscape over space and time.Discussion: Despite the recent emergence of some promising biomarkers for periampullary cancer, there has been a lack of success in clinical implementation. Cancer cells continuously adapt and become resistant to treatment during chemotherapy. To be able to keep pace with and hopefully overtake this rapid evolution we must, with the help of new diagnostic tools, be ready to adapt and alter treatment accordingly. It seems to us that the only way forward is to gain a better understanding of the dynamics of the disease during treatment. With insights gained from the CHAMP study we hope to find answers to key questions in this largely unexplored territory.Trial Registration: This study has been registered 30th October 2018 at clinicaltrials.gov as NCT03724994. [ABSTRACT FROM AUTHOR]- Published
- 2020
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229. Neuroblastoma patient-derived orthotopic xenografts reflect the microenvironmental hallmarks of aggressive patient tumours.
- Author
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Braekeveldt, Noémie, Wigerup, Caroline, Tadeo, Irene, Beckman, Siv, Sandén, Caroline, Jönsson, Jimmie, Erjefält, Jonas S., Berbegall, Ana P., Börjesson, Anna, Backman, Torbjörn, Øra, Ingrid, Navarro, Samuel, Noguera, Rosa, Gisselsson, David, Påhlman, Sven, and Bexell, Daniel
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NEUROBLASTOMA , *XENOGRAFTS , *TUMORS in children , *DRUG use testing , *PATIENTS , *TUMOR treatment , *THERAPEUTICS , *ANIMAL experimentation , *BIOLOGICAL models , *BLOOD vessels , *CELL physiology , *GENETIC polymorphisms , *MICE , *PATHOLOGIC neovascularization , *GENOTYPES - Abstract
Treatment of high-risk childhood neuroblastoma is a clinical challenge which has been 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. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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230. Activation of human telomerase reverse transcriptase through gene fusion in clear cell sarcoma of the kidney.
- Author
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Karlsson, Jenny, Lilljebjörn, Henrik, Holmquist Mengelbier, Linda, Valind, Anders, Rissler, Marianne, Øra, Ingrid, Fioretos, Thoas, and Gisselsson, David
- Subjects
- *
TELOMERASE reverse transcriptase , *RENAL cancer , *NUCLEOTIDE sequence , *RNA sequencing , *MONOOXYGENASES , *TRYPTOPHAN - Abstract
Clear cell sarcoma of the kidney (CCSK) is a rare tumor type affecting infants and young children. Most CCSKs display few genomic aberrations, and no general underlying mechanism for tumor initiation has yet been identified, although a YWHAE-NUTM2B/NUTM2E fusion gene has been observed in a minority of cases. We performed RNA-sequencing of 22 CCSKs to investigate the presence of additional fusion transcripts. The presence of the YWHAE-NUTM2B/NUTM2E fusion was confirmed in two cases . In addition, a novel IRX2-TERT fusion transcript was identified in one case. SNP-array analyses revealed the underlying event to be an interstitial deletion in the short arm of chromosome 5 (5p15.33). TERT was dramatically upregulated under the influence of the IRX2 promoter. In line with TERT expression being driven by active IRX2 regulatory elements, we found a high expression of IRX2 in CCSKs irrespective of fusion gene status. IRX2 was also expressed in human fetal kidney – the presumed tissue of origin for CCSK. We conclude that in addition to promoter mutations and epigenetic events, TERT can also be activated in tumors via formation of fusion transcripts. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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231. Current and emerging sequencing-based tools for precision cancer medicine.
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Edsjö A, Gisselsson D, Staaf J, Holmquist L, Fioretos T, Cavelier L, and Rosenquist R
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- Humans, Child, Mutation, Genomics methods, High-Throughput Nucleotide Sequencing methods, Precision Medicine methods, Neoplasms diagnosis, Neoplasms genetics, Neoplasms therapy
- 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., Competing Interests: Declaration of competing interest A.E has received honoraria from Amgen, AstraZeneca, Bayer, Diaceutics, and Roche. R.R. has received honoraria from AbbVie, AstraZeneca, Illumina, Janssen and Roche. T.F. is a co-founder and scientific advisor of the companies Qlucore AB, Cantargia AB, and Lead Biologics Intl, and has received honoraria from Illumina Inc., (Copyright © 2024. Published by Elsevier Ltd.)
- Published
- 2024
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232. Diagnostic yield and clinical impact of germline sequencing in children with CNS and extracranial solid tumors-a nationwide, prospective Swedish study.
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Tesi B, Robinson KL, Abel F, Díaz de Ståhl T, Orrsjö S, Poluha A, Hellberg M, Wessman S, Samuelsson S, Frisk T, Vogt H, Henning K, Sabel M, Ek T, Pal N, Nyman P, Giraud G, Wille J, Pronk CJ, Norén-Nyström U, Borssén M, Fili M, Stålhammar G, Herold N, Tettamanti G, Maya-Gonzalez C, Arvidsson L, Rosén A, Ekholm K, Kuchinskaya E, Hallbeck AL, Nordling M, Palmebäck P, Kogner P, Smoler GK, Lähteenmäki P, Fransson S, Martinsson T, Shamik A, Mertens F, Rosenquist R, Wirta V, Tham E, Grillner P, Sandgren J, Ljungman G, Gisselsson D, Taylan F, and Nordgren A
- Abstract
Background: Childhood cancer predisposition (ChiCaP) syndromes are increasingly recognized as contributing factors to childhood cancer development. Yet, due to variable availability of germline testing, many children with ChiCaP might go undetected today. We report results from the nationwide and prospective ChiCaP study that investigated diagnostic yield and clinical impact of integrating germline whole-genome sequencing (gWGS) with tumor sequencing and systematic phenotyping in children with solid tumors., Methods: gWGS was performed in 309 children at diagnosis of CNS (n = 123, 40%) or extracranial (n = 186, 60%) solid tumors and analyzed for disease-causing variants in 189 known cancer predisposing genes. Tumor sequencing data were available for 74% (227/309) of patients. In addition, a standardized clinical assessment for underlying predisposition was performed in 95% (293/309) of patients., Findings: The prevalence of ChiCaP diagnoses was 11% (35/309), of which 69% (24/35) were unknown at inclusion (diagnostic yield 8%, 24/298). A second-hit and/or relevant mutational signature was observed in 19/21 (90%) tumors with informative data. ChiCaP diagnoses were more prevalent among patients with retinoblastomas (50%, 6/12) and high-grade astrocytomas (37%, 6/16), and in those with non-cancer related features (23%, 20/88), and ≥2 positive ChiCaP criteria (28%, 22/79). ChiCaP diagnoses were autosomal dominant in 80% (28/35) of patients, yet confirmed de novo in 64% (18/28). The 35 ChiCaP findings resulted in tailored surveillance (86%, 30/35) and treatment recommendations (31%, 11/35)., Interpretation: Overall, our results demonstrate that systematic phenotyping, combined with genomics-based diagnostics of ChiCaP in children with solid tumors is feasible in large-scale clinical practice and critically guides personalized care in a sizable proportion of patients., Funding: The study was supported by the Swedish Childhood Cancer Fund and the Ministry of Health and Social Affairs., Competing Interests: BT, FA, ET, and AN received support from the Swedish Childhood Cancer Fund (BT: TJ2018-0042; FA: KP2021-0010; ET: TJ2021-0125; AN: KP2019-0024, PR2019-0027, TJ2019-0013) and the Swedish Cancer Fund (FA: 21 1540 Fk 01 H; ET: 22 2451Fk; AN: 22 2057Pj). BT, ET and AN received support from Region Stockholm (BT: FoUI-985957; ET: FoUI-973659; AN: 5010124 ALF, 520136 ALF). AN received support from The Swedish Research Council (2021-02860). MB received honoraria for lectures by the Swedish Childhood Cancer Fund. GS served as advisor for trial design for Cyxone AB, Sweden. NH served as Chair of NOPHO Scientific Committee and Young NOPHO without retribution. RR received honoraria from AbbVie, AstraZeneca, Janssen, Illumina, and Roche. DG received grants from Swedish Ministry of Health and Social Affairs for GMS Childhood Cancer and is Vice dean for internationalization and recruitment, Faculty of Medicine, Lund University. AN received also funding from the Cancer Society of Stockholm, Stiftelsen Frimurare Barnhuset i Stockholm, Hållsten research foundation, Berth von Kantzow foundation and is board member of Sävstaholm foundation, Ågrenska foundation, Sällsyntafonden. All other authors have no conflict of interest to declare., (© 2024 The Author(s).)
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- 2024
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233. Hallmark discoveries in the biology of Wilms tumour.
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Perotti D, Williams RD, Wegert J, Brzezinski J, Maschietto M, Ciceri S, Gisselsson D, Gadd S, Walz AL, Furtwaengler R, Drost J, Al-Saadi R, Evageliou N, Gooskens SL, Hong AL, Murphy AJ, Ortiz MV, O'Sullivan MJ, Mullen EA, van den Heuvel-Eibrink MM, Fernandez CV, Graf N, Grundy PE, Geller JI, Dome JS, Perlman EJ, Gessler M, Huff V, and Pritchard-Jones K
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- Humans, Neoplasm Recurrence, Local, Biomarkers, Biology, Kidney Neoplasms therapy, Wilms Tumor therapy
- Abstract
The modern study of Wilms tumour was prompted nearly 50 years ago, when Alfred Knudson proposed the 'two-hit' model of tumour development. Since then, the efforts of researchers worldwide have substantially expanded our knowledge of Wilms tumour biology, including major advances in genetics - from cloning the first Wilms tumour gene to high-throughput studies that have revealed the genetic landscape of this tumour. These discoveries improve understanding of the embryonal origin of Wilms tumour, familial occurrences and associated syndromic conditions. Many efforts have been made to find and clinically apply prognostic biomarkers to Wilms tumour, for which outcomes are generally favourable, but treatment of some affected individuals remains challenging. Challenges are also posed by the intratumoural heterogeneity of biomarkers. Furthermore, preclinical models of Wilms tumour, from cell lines to organoid cultures, have evolved. Despite these many achievements, much still remains to be discovered: further molecular understanding of relapse in Wilms tumour and of the multiple origins of bilateral Wilms tumour are two examples of areas under active investigation. International collaboration, especially when large tumour series are required to obtain robust data, will help to answer some of the remaining unresolved questions., (© 2023. Springer Nature Limited.)
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- 2024
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234. A Gradual Transition Toward Anaplasia in Wilms Tumor Through Tolerance to Genetic Damage.
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Uno K, Rastegar B, Jansson C, Durand G, Valind A, Chattopadhyay S, Bertolotti A, Ciceri S, Spreafico F, Collini P, Perotti D, Mengelbier LH, and Gisselsson D
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- Humans, Anaplasia genetics, Mutation, Prognosis, DNA, Kidney Neoplasms genetics, Kidney Neoplasms pathology, Wilms Tumor genetics, Wilms Tumor drug therapy, Wilms Tumor pathology
- Abstract
Patients with Wilms tumor (WT) in general have excellent survival, but the prognosis of patients belonging to the subgroup of WT with diffuse anaplasia (DA) is poor due to frequent resistance to chemotherapy. We hypothesized that DA WT cells might undergo changes, such as acquiring a persistent tolerance to DNA damage and copy number aberrations (CNAs), which could eventually lead to their resistance to chemotherapy treatment. Tissue sections from chemotherapy-treated DA WTs (n = 12) were compared with chemotherapy-treated nonanaplastic WTs (n = 15) in a tissue microarray system, enabling analysis of 769 tumor regions. All regions were scored for anaplastic features and immunohistochemistry was used to quantify p53 expression, proliferation index (Ki67), and DNA double-strand breaks (γH2AX). CNAs were assessed by array-based genotyping and TP53 mutations using targeted sequencing. Proliferation index and the frequency of DNA double-strand breaks (γH2AX dot expression) increased with higher anaplasia scores. Almost all (95.6%) areas with full-scale anaplasia had TP53 mutations or loss of heterozygosity, along with an increased amount of CNAs. Interestingly, areas with wild-type TP53 with loss of heterozygosity and only one feature of anaplasia (anaplasia score 1) also had significantly higher proliferation indices, more DNA double-strand breaks, and more CNAs than regions without any anaplastic features (score 0); such areas may be preanaplastic cell populations under selective pressure for TP53 mutations. In conclusion, we suggest that chemoresistance of DA WTs may be partly explained by a high proliferative capability of anaplastic cells, which also have a high burden of double-stranded DNA breaks and CNAs, and that there is a gradual emergence of anaplasia in WT., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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235. Weaponized genomics: potential threats to international and human security.
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Chattopadhyay S, Ingesson T, Rinaldi A, Larsson O, Widen JJ, Almqvist J, and Gisselsson D
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- Humans, Computer Security, Global Health, Genomics
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- 2024
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236. Wargaming cancer: a strategy for future precision oncology?
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Ingesson T and Gisselsson D
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- Humans, Precision Medicine, Medical Oncology, Neoplasms therapy, Neoplasms drug therapy
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Development of drug resistance is a mounting problem in precision oncology, demanding a rethink of treatment strategy. Here, we apply concepts from military theory and espionage to the battle-like dynamics between cancer and its host, thereby identifying system vulnerabilities in cancer and ways of tricking cancer evolution into dead ends., Competing Interests: Declaration of interests No interests are declared., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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237. Resolving the Pathogenesis of Anaplastic Wilms Tumors through Spatial Mapping of Cancer Cell Evolution.
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Rastegar B, Andersson N, Petersson A, Karlsson J, Chattopadhyay S, Valind A, Jansson C, Durand G, Romerius P, Jirström K, Holmquist Mengelbier L, and Gisselsson D
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- Humans, Anaplasia genetics, Retrospective Studies, Phylogeny, Kidney Neoplasms pathology, Wilms Tumor genetics, Wilms Tumor pathology
- Abstract
Purpose: While patients with intermediate-risk (IR) Wilms tumors now have an overall survival (OS) rate of almost 90%, those affected by high-stage tumors with diffuse anaplasia have an OS of only around 50%. We here identify key events in the pathogenesis of diffuse anaplasia by mapping cancer cell evolution over anatomic space in Wilms tumors., Experimental Design: We spatially mapped subclonal landscapes in a retrospective cohort of 20 Wilms tumors using high-resolution copy-number profiling and TP53 mutation analysis followed by clonal deconvolution and phylogenetic reconstruction. Tumor whole-mount sections (WMS) were utilized to characterize the distribution of subclones across anatomically distinct tumor compartments., Results: Compared with non-diffuse anaplasia Wilms tumors, tumors with diffuse anaplasia showed a significantly higher number of genetically distinct tumor cell subpopulations and more complex phylogenetic trees, including high levels of phylogenetic species richness, divergence, and irregularity. All regions with classical anaplasia showed TP53 alterations. TP53 mutations were frequently followed by saltatory evolution and parallel loss of the remaining wild-type (WT) allele in different regions. Morphologic features of anaplasia increased with copy-number aberration (CNA) burden and regressive features. Compartments demarcated by fibrous septae or necrosis/regression were frequently (73%) associated with the emergence of new clonal CNAs, although clonal sweeps were rare within these compartments., Conclusions: Wilms tumors with diffuse anaplasia display significantly more complex phylogenies compared with non-diffuse anaplasia Wilms tumors, including features of saltatory and parallel evolution. The subclonal landscape of individual tumors was constrained by anatomic compartments, which should be considered when sampling tissue for precision diagnostics., (©2023 The Authors; Published by the American Association for Cancer Research.)
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- 2023
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238. Diagnostic Yield From a Nationwide Implementation of Precision Medicine for all Children With Cancer.
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Wadensten E, Wessman S, Abel F, Diaz De Ståhl T, Tesi B, Orsmark Pietras C, Arvidsson L, Taylan F, Fransson S, Vogt H, Poluha A, Pradhananga S, Hellberg M, Lagerstedt-Robinson K, Raj Somarajan P, Samuelsson S, Orrsjö S, Maqbool K, Henning K, Strid T, Ek T, Fagman H, Olsson Bontell T, Martinsson T, Puls F, Kogner P, Wirta V, Pronk CJ, Wille J, Rosenquist R, Nistér M, Mertens F, Sabel M, Norén-Nyström U, Grillner P, Nordgren A, Ljungman G, Sandgren J, and Gisselsson D
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- Humans, Child, Neoplasm Recurrence, Local, Gene Fusion, Genomics, Precision Medicine, Carcinoma
- Abstract
Purpose: Several studies have indicated that broad genomic characterization of childhood cancer provides diagnostically and/or therapeutically relevant information in selected high-risk cases. However, the extent to which such characterization offers clinically actionable data in a prospective broadly inclusive setting remains largely unexplored., Methods: We implemented prospective whole-genome sequencing (WGS) of tumor and germline, complemented by whole-transcriptome sequencing (RNA-Seq) for all children diagnosed with a primary or relapsed solid malignancy in Sweden. Multidisciplinary molecular tumor boards were set up to integrate genomic data in the clinical decision process along with a medicolegal framework enabling secondary use of sequencing data for research purposes., Results: During the study's first 14 months, 118 solid tumors from 117 patients were subjected to WGS, with complementary RNA-Seq for fusion gene detection in 52 tumors. There was no significant geographic bias in patient enrollment, and the included tumor types reflected the annual national incidence of pediatric solid tumor types. Of the 112 tumors with somatic mutations, 106 (95%) exhibited alterations with a clear clinical correlation. In 46 of 118 tumors (39%), sequencing only corroborated histopathological diagnoses, while in 59 cases (50%), it contributed to additional subclassification or detection of prognostic markers. Potential treatment targets were found in 31 patients (26%), most commonly ALK mutations/fusions (n = 4), RAS/RAF/MEK/ERK pathway mutations (n = 14), FGFR1 mutations/fusions (n = 5), IDH1 mutations (n = 2), and NTRK2 gene fusions (n = 2). In one patient, the tumor diagnosis was revised based on sequencing. Clinically relevant germline variants were detected in 8 of 94 patients (8.5%)., Conclusion: Up-front, large-scale genomic characterization of pediatric solid malignancies provides diagnostically valuable data in the majority of patients also in a largely unselected cohort.
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- 2023
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239. Systematic orientation of fresh rectal suction biopsies improves histopathological diagnostics in hirschsprung's disease - a method description and preliminary report.
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Fransson E, Gottberg E, Mitev RM, Gisselsson D, Hagelsteen K, Tofft L, Stenström P, and Granéli C
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- Child, Humans, Infant, Biopsy, Case-Control Studies, Immunohistochemistry, Suction, Hirschsprung Disease diagnosis, Hirschsprung Disease pathology, Rectum pathology
- 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., (© 2023. The Author(s).)
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- 2023
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240. Tumor biology, biomarkers, and liquid biopsy in pediatric renal tumors.
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Walz AL, Maschietto M, Crompton B, Evageliou N, Dix D, Tytgat G, Gessler M, Gisselsson D, Daw NC, and Wegert J
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- Child, Humans, Liquid Biopsy, Biomarkers, Tumor genetics, Biology, Kidney Neoplasms pathology, Wilms Tumor pathology
- 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., (© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)
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- 2023
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241. Modelling evolution at the boundaries of solid tumours.
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Chattopadhyay S and Gisselsson D
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- Humans, Neoplasms
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- 2023
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242. Histopathological dimensions differ between aganglionic and ganglionic bowel wall in children with Hirschsprung's disease.
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Graneli C, Patarroyo S, Mitev RM, Gisselsson D, Gottberg E, Erlöv T, Jansson T, Hagelsteen K, Cinthio M, and Stenström P
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- Child, Humans, Infant, Intestines pathology, Ganglia pathology, Hirschsprung Disease genetics
- Abstract
Background: In the validation of new imaging technology for children with Hirschsprung's disease (HSCR), basic anatomical parameters of the bowel wall must be established specifically for this patient group., Aim: To explore differences in histoanatomical layers of bowel wall, comparing ganglionic and aganglionic bowel walls, and to examine if the bowel wall thickness is linked to patient weight., Methods: This was an observational study of bowel specimens from children weighing 0-10 kg, operated on consecutively during 2018-2020. Ganglionic and aganglionic bowel walls were measured in digitalized microscopy images from 10 sites per trans-sectional specimen and compared regarding the thickness of their histoanatomical layers., Results: Bowel walls were measured in 21 children. Full bowel wall thickness did not differ between aganglionic and ganglionic bowel (2.20 vs 2.04; p = 0.802) while weight at surgery correlated positively with both ganglionic and aganglionic bowel wall thickness (r = 0.688 and 0.849, respectively), and age at surgery with ganglionic bowel wall thickness (r = 0.517). In aganglionic segments, the muscularis externa layer was thicker compared to that in ganglionosis (0.45 vs 0.31 mm, p = 0.012) whereas the muscularis interna was thinner (0.45 vs 0.62 mm, p < 0.001). A diagnostic index was identified whereby a lower ratio of muscularis interna/externa thickness followed by a thinner muscularis interna differed between aganglionic and ganglionic bowel in all specimens., Conclusion: Thicknesses of the bowel wall's muscle layers differ between aganglionic and ganglionic bowel walls in children with HSCR. These findings support a diagnostic index that could be validated for transfer to instant diagnostic imaging techniques., Level of Evidence: Diagnostic: 3., (© 2022. The Author(s).)
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- 2022
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243. Clinically relevant treatment of PDX models reveals patterns of neuroblastoma chemoresistance.
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Mañas A, Aaltonen K, Andersson N, Hansson K, Adamska A, Seger A, Yasui H, van den Bos H, Radke K, Esfandyari J, Bhave MS, Karlsson J, Spierings D, Foijer F, Gisselsson D, and Bexell D
- Abstract
Chemotherapy resistance and relapses are common in high-risk neuroblastoma (NB). Here, we developed a clinically relevant in vivo treatment protocol mimicking the first-line five-chemotherapy treatment regimen of high-risk NB and applied this protocol to mice with MYCN -amplified NB patient-derived xenografts (PDXs). Genomic and transcriptomic analyses were used to reveal NB chemoresistance mechanisms. Intrinsic resistance was associated with high genetic diversity and an embryonic phenotype. Relapsed NB with acquired resistance showed a decreased adrenergic phenotype and an enhanced immature mesenchymal-like phenotype, resembling multipotent Schwann cell precursors. NBs with a favorable treatment response presented a lineage-committed adrenergic phenotype similar to normal neuroblasts. Novel integrated phenotypic gene signatures reflected treatment response and patient prognosis. NB organoids established from relapsed PDX tumors retained drug resistance, tumorigenicity, and transcriptional cell states. This work sheds light on the mechanisms of NB chemotherapy response and emphasizes the importance of transcriptional cell states in chemoresistance.
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- 2022
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244. Implementing precision medicine in a regionally organized healthcare system in Sweden.
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Fioretos T, Wirta V, Cavelier L, Berglund E, Friedman M, Akhras M, Botling J, Ehrencrona H, Engstrand L, Helenius G, Fagerqvist T, Gisselsson D, Gruvberger-Saal S, Gyllensten U, Heidenblad M, Höglund K, Jacobsson B, Johansson M, Johansson Å, Soller MJ, Landström M, Larsson P, Levin LÅ, Lindstrand A, Lovmar L, Lyander A, Melin M, Nordgren A, Nordmark G, Mölling P, Palmqvist L, Palmqvist R, Repsilber D, Sikora P, Stenmark B, Söderkvist P, Stranneheim H, Strid T, Wheelock CE, Wadelius M, Wedell A, Edsjö A, and Rosenquist R
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- Sweden, Delivery of Health Care, Precision Medicine
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- 2022
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245. Clinical-pathological features in placentas of pregnancies with SARS-CoV-2 infection and adverse outcome: case series with and without congenital transmission.
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Zaigham M, Gisselsson D, Sand A, Wikström AK, von Wowern E, Schwartz DA, Iorizzo L, Nelander M, Blomberg M, Papadogiannakis N, Holmström S, Leijonhfvud Å, and Sengpiel V
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- Cesarean Section, Female, Fetal Distress, Humans, Infant, Newborn, Infectious Disease Transmission, Vertical, Placenta blood supply, Pregnancy, Retrospective Studies, SARS-CoV-2, Stillbirth epidemiology, COVID-19, Pregnancy Complications, Infectious diagnosis
- Abstract
Objective: To correlate clinical outcomes to pathology in SARS-CoV-2 infected placentas in stillborn and live-born infants presenting with fetal distress., Design: Retrospective, observational., Setting: Nationwide., Population: Five stillborn and nine live-born infants from 13 pregnant women infected with SARS-CoV-2 seeking care at seven different maternity units in Sweden., Methods: Clinical outcomes and placental pathology were studied in 14 cases (one twin pregnancy) of maternal SARS-CoV-2 infection with impaired fetal outcome. Outcomes were correlated to placental pathology in order to investigate the impact of virus-related pathology on the villous capillary endothelium, trophoblast and other cells., Main Outcome Measures: Maternal and fetal clinical outcomes and placental pathology in stillborn and live-born infants., Results: Reduced fetal movements were reported (77%) and time from onset of maternal COVID-19 symptoms to signs of fetal distress among live-born infants was 6 (3-12) days and to diagnosis of stillbirth 11 (2-25) days. Two of the live-born infants died during the postnatal period. Signs of fetal distress led to emergency caesarean section in all live-born infants with umbilical cord blood gases and low Apgar scores confirming intrauterine hypoxia. Five stillborn and one live-born neonate had confirmed congenital transmission. Massive perivillous fibrinoid deposition, intervillositis and trophoblast necrosis were associated with SARS-CoV-2 placental infection and congenital transmission., Conclusions: SARS-CoV-2 can cause rapid placental dysfunction with subsequent acute fetal hypoxia leading to intrauterine fetal compromise. Associated placental pathology included massive perivillous fibrinoid deposition, intervillositis and trophoblast degeneration., (© 2022 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)
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- 2022
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246. Delineating the intra-patient heterogeneity of molecular alterations in treatment-naïve colorectal cancer with peritoneal carcinomatosis.
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Siesing C, Petersson A, Ulfarsdottir T, Chattopadhyay S, Nodin B, Eberhard J, Brändstedt J, Syk I, Gisselsson D, and Jirström K
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- Combined Modality Therapy, DNA Copy Number Variations, Humans, Hyperthermia, Induced, Lymphatic Metastasis, Neoplasm Recurrence, Local pathology, Prognosis, RNA-Binding Proteins metabolism, Survival Rate, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, Colorectal Neoplasms therapy, Peritoneal Neoplasms genetics, Peritoneal Neoplasms pathology, Peritoneal Neoplasms therapy
- Abstract
In a non-negligible number of patients with metastatic colorectal cancer (mCRC), the peritoneum is the predominant site of dissemination. Cure can be achieved by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), but this procedure is associated with long-term morbidity and high relapse rates. Thus, there is a pressing need for improved therapeutic strategies and complementary biomarkers. The present study explored the molecular heterogeneity in mCRC with peritoneal carcinomatosis (PC), and the potential clinical implications thereof. Multi-region immunohistochemical profiling and deep targeted DNA-sequencing was performed on chemotherapy-naïve tumours from seven patients with synchronous colorectal PC who underwent CRS and HIPEC. In total, 88 samples (5-19 per patient) were analysed, representing primary tumour, lymph node metastases, tumour deposits, PC and liver metastases. Expression of special AT-rich sequence-binding protein 2 (SATB2), a marker of colorectal lineage, was lacking in the majority of cases, and a conspicuous intra-patient heterogeneity was denoted for expression of the proposed prognostic and predictive biomarker RNA-binding motif protein 3 (RBM3). Loss of mismatch repair proteins MLH1 and PSM2, observed in one case, was concordant with microsatellite instability and the highest tumour mutational burden. When present in a patient, mutations in key CRC driver genes, i.e., KRAS, APC and TP53, were homogenously distributed across all samples, while less common mutations were more heterogenous. On the same note, copy number variations showed intra-patient as well inter-patient heterogeneity. In two out of seven cases, hierarchical clustering revealed that samples from the PC and lymph node metastases were more similar to each other than to the primary tumour. In summary, these findings should encourage additional studies addressing the potential distinctiveness of mCRC with PC, which might pave the way for improved personalized treatment of these patients., (© 2022. The Author(s).)
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- 2022
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247. Amplification of ERBB2 (HER2) in embryonal rhabdomyosarcoma: A potential treatment target in rare cases?
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Mitra S, Sydow S, Magnusson L, Piccinelli P, Törnudd L, Øra I, Ljungman G, Sandgren J, Gisselsson D, and Mertens F
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- Antineoplastic Agents, Immunological pharmacology, Child, Child, Preschool, Female, Head and Neck Neoplasms genetics, Head and Neck Neoplasms pathology, Head and Neck Neoplasms therapy, Humans, Receptor, ErbB-2 antagonists & inhibitors, Receptor, ErbB-2 metabolism, Rhabdomyosarcoma, Embryonal pathology, Rhabdomyosarcoma, Embryonal therapy, Standard of Care, Trastuzumab pharmacology, Treatment Outcome, Vaginal Neoplasms genetics, Vaginal Neoplasms pathology, Vaginal Neoplasms therapy, Gene Amplification, Receptor, ErbB-2 genetics, Rhabdomyosarcoma, Embryonal genetics
- Abstract
The ERBB2 gene encodes a receptor tyrosine kinase also known as HER2. The gene is amplified and overexpressed in one-fifth of breast carcinomas; patients with such tumors benefit from targeted treatment with trastuzumab or other drugs blocking the receptor. In addition, ERBB2 has been shown to be amplified and/or overexpressed in a variety of other malignancies. Notably, both alveolar and embryonal rhabdomyosarcoma (RMS), especially in children, often show increased expression of ERBB2. Although high-level amplification of the gene has not been described in RMS, its frequent expression at the cell surface of RMS cells has been exploited for chimeric antigen receptor T-cell (CAR T)-based treatment strategies. We here describe two cases of pediatric, fusion-negative embryonal RMS with high-level amplification of the ERBB2 gene. One patient is currently treated with conventional chemotherapy for a recently detected standard risk RMS, whereas the other patient died from metastatic disease. Both tumors displayed focal amplicons (210 and 274 Kb, respectively) in chromosome band 17q12, with proximal and distal borders corresponding to those typically seen in breast cancer. In both tumors, the ERBB2 amplicon correlated with high expression at the RNA and protein levels. Thus, breast cancer-like ERBB2 amplification is a very rare, but recurrent feature of pediatric RMS, and should be exploited as an alternative treatment target., (© 2021 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)
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- 2022
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248. Ultra high frequency ultrasonography to distinguish ganglionic from aganglionic bowel wall in Hirschsprung disease: A first report.
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Granéli C, Erlöv T, Mitev RM, Kasselaki I, Hagelsteen K, Gisselsson D, Jansson T, Cinthio M, and Stenström P
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- Child, Colon, Colon, Sigmoid, Humans, Infant, Rectum diagnostic imaging, Ultrasonography, Hirschsprung Disease diagnostic imaging, Hirschsprung Disease surgery
- Abstract
Background/purpose: In Hirschsprung disease (HD) surgery, confirming ganglionic bowel is essential. A faster diagnostic method than the current frozen biopsy is desirable. This study investigated whether aganglionic and ganglionic intestinal wall can be distinguished from each other by ultra high frequency ultrasound (UHF ultrasound)., Methods: In an HD center during 2019, intestinal walls of recto-sigmoid specimens from HD patients were examined ex vivo with a 70 MHz UHF ultrasound transducer. Data from four sites were described. Histopathologic analysis was compared to the ultrasonography outcome at each site. Each patient's specimen served as its own control., Results: 11 resected recto-sigmoid specimens (median 20 cm long [range 6.5-33]) with transition zones of 5 cm (2-11 cm) were taken from children aged 22 days (13-48) weighing 3668 g (3500-5508); 44 key sites were analyzed. There was full concordance for 42/44 (95%) key sites and 10 of 11 (91%) specimens. The specimen with discordance of two key sites contained a segment of aganglionosis (3 cm) and a transition zone (1 cm): the site discordance was limited to the transition zone ends., Conclusions: This first report on UHF ultrasound in recto-sigmoid HD shows promising results in identifying aganglionosis, transition zones and ganglionic bowel. Further in vivo studies are required., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2021. Published by Elsevier Inc.)
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- 2021
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249. Clonal competition within complex evolutionary hierarchies shapes AML over time.
- Author
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Sandén C, Lilljebjörn H, Orsmark Pietras C, Henningsson R, Saba KH, Landberg N, Thorsson H, von Palffy S, Peña-Martinez P, Högberg C, Rissler M, Gisselsson D, Lazarevic V, Juliusson G, Ågerstam H, and Fioretos T
- Subjects
- Adult, Aged, Aged, 80 and over, Animals, Disease Progression, Female, Humans, Leukemia, Myeloid, Acute pathology, Male, Mice, Middle Aged, Mutation, Exome Sequencing, Clonal Evolution, Leukemia, Myeloid, Acute genetics
- Abstract
Clonal heterogeneity and evolution has major implications for disease progression and relapse in acute myeloid leukemia (AML). To model clonal dynamics in vivo, we serially transplanted 23 AML cases to immunodeficient mice and followed clonal composition for up to 15 months by whole-exome sequencing of 84 xenografts across two generations. We demonstrate vast changes in clonality that both progress and reverse over time, and define five patterns of clonal dynamics: Monoclonal, Stable, Loss, Expansion and Burst. We also show that subclonal expansion in vivo correlates with a more adverse prognosis. Furthermore, clonal expansion enabled detection of very rare clones with AML driver mutations that were undetectable by sequencing at diagnosis, demonstrating that the vast majority of AML cases harbor multiple clones already at diagnosis. Finally, the rise and fall of related clones enabled deconstruction of the complex evolutionary hierarchies of the clones that compete to shape AML over time.
- Published
- 2020
- Full Text
- View/download PDF
250. Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer.
- Author
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Karlsson J, Valind A, Holmquist Mengelbier L, Bredin S, Cornmark L, Jansson C, Wali A, Staaf J, Viklund B, Øra I, Börjesson A, Backman T, Braekeveldt N, Sandstedt B, Pal N, Isaksson A, Lackner BG, Jonson T, Bexell D, and Gisselsson D
- Subjects
- Child, Chromosomes genetics, Evolution, Molecular, Gene Rearrangement genetics, Humans, Tumor Suppressor Protein p53 genetics, Mutation genetics, Neoplasms genetics
- Abstract
A major challenge to personalized oncology is that driver mutations vary among cancer cells inhabiting the same tumor. Whether this reflects principally disparate patterns of Darwinian evolution in different tumor regions has remained unexplored
1-5 . We mapped the prevalence of genetically distinct clones over 250 regions in 54 childhood cancers. This showed that primary tumors can simultaneously follow up to four evolutionary trajectories over different anatomic areas. The most common pattern consists of subclones with very few mutations confined to a single tumor region. The second most common is a stable coexistence, over vast areas, of clones characterized by changes in chromosome numbers. This is contrasted by a third, less frequent, pattern where a clone with driver mutations or structural chromosome rearrangements emerges through a clonal sweep to dominate an anatomical region. The fourth and rarest pattern is the local emergence of a myriad of clones with TP53 inactivation. Death from disease was limited to tumors exhibiting the two last, most dynamic patterns.- Published
- 2018
- Full Text
- View/download PDF
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