| 1. |
- Holmquist Mengelbier, Linda, et al.
(författare)
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Intratumoral genome diversity parallels progression and predicts outcome in pediatric cancer.
- 2015
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Tidskriftsartikel (refereegranskat)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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| 2. |
- Karlsson, Jenny, et al.
(författare)
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Four evolutionary trajectories underlie genetic intratumoral variation in childhood cancer
- 2018
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:7, s. 944-950
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Tidskriftsartikel (refereegranskat)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 unexplored1–5. 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.
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| 3. |
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| 4. |
- Andersson, Jesper L, et al.
(författare)
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A method for coregistration of PET and MR brain images
- 1995
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Ingår i: Journal of Nuclear Medicine. - 0161-5505 .- 1535-5667. ; 36:7, s. 1307-1315
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Tidskriftsartikel (refereegranskat)abstract
- Combining MRI morphological data with functional PET data offers significant advantages in research as well as in many clinical situations. Automatic methods are needed, however, to coregister the data from the two modalities.METHODS:Simulated PET images were created by simple and automatic segmentation of MR images followed by the assignment of different uptake values to various tissue types. The simulated PET images were registered to actual PET images using a pixel-by-pixel, PET-PET registration method. The transformation matrix was then applied to the MR images. The method was used to register MRI data to PET transmission scans and emission scans obtained with FDG, nomifensine and raclopride. Validation was performed by comparing the results to those obtained by matching internal points manually defined in both volumes.RESULTS:Emission and transmission PET images were successfully registered to MR data. Comparison to the manual method indicated a registration accuracy on the order of 1-2 mm in each direction. No difference in accuracy between the different tracers was found. The error sensitivity for the method's assumptions seemed to be sufficiently low to allow complete automation of the method.CONCLUSION:We present a rapid, robust and fully automated method to register PET and MR brain images with sufficient accuracy for most clinical applications.
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| 5. |
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| 6. |
- Andersson, Natalie, et al.
(författare)
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DEVOLUTION—A method for phylogenetic reconstruction of aneuploid cancers based on multiregional genotyping data
- 2021
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Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4
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Tidskriftsartikel (refereegranskat)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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| 7. |
- Andersson, Natalie, et al.
(författare)
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Extensive clonal branching shapes the evolutionary history of high-risk pediatric cancers
- 2020
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Ingår i: Cancer Research. - 1538-7445. ; 80:7, s. 1512-1523
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Tidskriftsartikel (refereegranskat)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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| 8. |
- Aziz, Q, et al.
(författare)
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Identification of human brain loci processing esophageal sensation using positron emission tomography
- 1997
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Ingår i: Gastroenterology. - 0016-5085 .- 1528-0012. ; 113:1, s. 50-59
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS:Brain loci that process human esophageal sensation remain unidentified. The aim of this study was to identify the brain loci that process nonpainful and painful human esophageal sensation.METHODS:In 8 healthy subjects (7 men; age range, 24-47 years), distal esophageal stimulation was performed by repeatedly inflating a balloon at volumes that produced either no sensation, definite sensation, or pain. Two positron emission tomography scans were performed for each sensation using H2(15)O. Magnetic resonance brain scans were also performed in each subject, and the positron emission tomography data were coregistered with magnetic resonance scans. Analysis of covariance-corrected t images showing the contrasts definite sensation-baseline, pain-baseline, and pain-definite sensation were created.RESULTS:Nonpainful stimulation elicited bilateral activations along the central sulcus, insular cortex, and frontal/parietal operculum (P < 0.01). Painful stimulation produced more intense activations of the same areas and additional activation of the right anterior insular cortex and the anterior cingulate gyrus. Multiple areas of decreased activation were also observed; prominent among these was the right prefrontal cortex, which was inhibited during both nonpainful and painful stimulation.CONCLUSIONS:Esophageal sensation activates bilaterally the insula, primary somatosensory cortex, and operculum. The right anterior insular cortex and anterior cingulate gyrus process esophageal pain.
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| 9. |
- Chattopadhyay, Subhayan, et al.
(författare)
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Tracing the evolution of aneuploid cancers by multiregional sequencing with CRUST
- 2021
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Ingår i: Briefings in Bioinformatics. - : Oxford University Press (OUP). - 1477-4054 .- 1467-5463. ; 22:6
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Tidskriftsartikel (refereegranskat)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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