| 1. |
- Northcott, Paul A, et al.
(författare)
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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 511:7510, s. 428-428
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Tidskriftsartikel (refereegranskat)abstract
- Medulloblastoma is a highly malignant paediatric brain tumour currently treated with a combination of surgery, radiation and chemotherapy, posing a considerable burden of toxicity to the developing child. Genomics has illuminated the extensive intertumoral heterogeneity of medulloblastoma, identifying four distinct molecular subgroups. Group 3 and group 4 subgroup medulloblastomas account for most paediatric cases; yet, oncogenic drivers for these subtypes remain largely unidentified. Here we describe a series of prevalent, highly disparate genomic structural variants, restricted to groups 3 and 4, resulting in specific and mutually exclusive activation of the growth factor independent 1 family proto-oncogenes, GFI1 and GFI1B. Somatic structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements, including super-enhancers, instigating oncogenic activity. Our results, supported by evidence from mouse models, identify GFI1 and GFI1B as prominent medulloblastoma oncogenes and implicate 'enhancer hijacking' as an efficient mechanism driving oncogene activation in a childhood cancer.
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| 2. |
- Alexandrov, Ludmil B., et al.
(författare)
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Signatures of mutational processes in human cancer
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 500:7463, s. 415-421
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Tidskriftsartikel (refereegranskat)abstract
- All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
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| 3. |
- Försti, Asta, et al.
(författare)
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Pedigree based DNA sequencing pipeline for germline genomes of cancer families
- 2016
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Ingår i: Hereditary Cancer in Clinical Practice. - : Springer Science and Business Media LLC. - 1731-2302 .- 1897-4287. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: In the course of our whole-genome sequencing efforts, we have developed a pipeline for analyzing germline genomes from Mendelian types of cancer pedigrees (familial cancer variant prioritization pipeline, FCVPP). Results: The variant calling step distinguishes two types of genomic variants: single nucleotide variants (SNVs) and indels, which undergo technical quality control. Mendelian types of variants are assumed to be rare and variants with frequencies higher that 0.1 % are screened out using human 1000 Genomes (Phase 3) and non-TCGA ExAC population data. Segregation in the pedigree allows variants to be present in affected family members and not in old, unaffected ones. The effectiveness of variant segregation depends on the number and relatedness of the family members: if over 5 third-degree (or more distant) relatives are available, the experience has shown that the number of likely variants is reduced from many hundreds to a few tens. These are then subjected to bioinformatics analysis, starting with the combined annotation dependent depletion (CADD) tool, which predicts the likelihood of the variant being deleterious. Different sets of individual tools are used for further evaluation of the deleteriousness of coding variants, 5' and 3' untranslated regions (UTRs), and intergenic variants. Conlusions: The likelihood of success of the present genomic pipeline in finding novel high- or medium-penetrant genes depends on many steps but first and foremost, the pedigree needs to be reasonably large and the assignments and diagnoses among the members need to be correct.
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| 4. |
- Hudson, Thomas J., et al.
(författare)
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International network of cancer genome projects
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Tidskriftsartikel (refereegranskat)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 5. |
- Kumar, Abhishek, et al.
(författare)
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Familial Cancer Variant Prioritization Pipeline version 2 (FCVPPv2) applied to a papillary thyroid cancer family
- 2018
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Whole-genome sequencing methods in familial cancer are useful to unravel rare clinically important cancer predisposing variants. Here, we present improvements in our pedigree-based familial cancer variant prioritization pipeline referred as FCVPPv2, including 12 tools for evaluating deleteriousness and 5 intolerance scores for missense variants. This pipeline is also capable of assessing non-coding regions by combining FANTOM5 data with sets of tools like Bedtools, ChromHMM, Miranda, SNPnexus and Targetscan. We tested this pipeline in a family with history of a papillary thyroid cancer. Only one variant causing an amino acid change G573R (dbSNP ID rs145736623, NM_019609.4:exon11:c.G1717A:p.G573R) in the carboxypeptidase gene CPXM1 survived our pipeline. This variant is located in a highly conserved region across vertebrates in the peptidase_M14 domain (Pfam ID PF00246). The CPXM1 gene may be involved in adipogenesis and extracellular matrix remodelling and it has been suggested to be a tumour suppressor in breast cancer. However, the presence of the variant in the ExAC database suggests it to be a rare polymorphism or a low-penetrance risk allele. Overall, our pipeline is a comprehensive approach for prediction of predisposing variants for high-risk cancer families, for which a functional characterization is a crucial step to confirm their role in cancer predisposition.
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| 6. |
- Partel, Gabriele, 1988-
(författare)
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Image and Data Analysis for Spatially Resolved Transcriptomics : Decrypting fine-scale spatial heterogeneity of tissue's molecular architecture
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Our understanding of the biological complexity in multicellular organisms has progressed at tremendous pace in the last century and even more in the last decades with the advent of sequencing technologies that make it possible to interrogate the genome and transcriptome of individual cells. It is now possible to even spatially profile the transcriptomic landscape of tissue architectures to study the molecular organization of tissue heterogeneity at subcellular resolution. Newly developed spatially resolved transcriptomic techniques are producing large amounts of high-dimensional image data with increasing throughput, that need to be processed and analysed for extracting biological relevant information that has the potential to lead to new knowledge and discoveries. The work included in this thesis aims to provide image and data analysis tools for serving this new developing field of spatially resolved transcriptomics to fulfill its purpose. First, an image analysis workflow is presented for processing and analysing images acquired with in situ sequencing protocols, aiming to extract and decode molecular features that map the spatial transcriptomic landscape in tissue sections. This thesis also presents computational methods to explore and analyse the decoded spatial gene expression for studying the spatial molecular heterogeneity of tissue architectures at different scales. In one case, it is demonstrated how dimensionality reduction and clustering of the decoded gene expression spatial profiles can be exploited and used to identify reproducible spatial compartments corresponding to know anatomical regions across mouse brain sections from different individuals. And lastly, this thesis presents an unsupervised computational method that leverages advanced deep learning techniques on graphs to model the spatial gene expression at cellular and subcellular resolution. It provides a low dimensional representation of spatial organization and interaction, finding functional units that in many cases correspond to different cell types in the local tissue environment, without the need for cell segmentation.
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| 7. |
- Prager, Isabel, et al.
(författare)
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NK cells switch from granzyme B to death receptor–mediated cytotoxicity during serial killing
- 2019
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 0022-1007 .- 1540-9538. ; 7:9, s. 2113-2127
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Tidskriftsartikel (refereegranskat)abstract
- NK cells eliminate virus-infected and tumor cells by releasing cytotoxic granules containing granzyme B (GrzB) or by engaging death receptors that initiate caspase cascades. The orchestrated interplay between both cell death pathways remains poorly defined. Here we simultaneously measure the activities of GrzB and caspase-8 in tumor cells upon contact with human NK cells. We observed that NK cells switch from inducing a fast GrzB-mediated cell death in their first killing events to a slow death receptor–mediated killing during subsequent tumor cell encounters. Target cell contact reduced intracellular GrzB and perforin and increased surface-CD95L in NK cells over time, showing how the switch in cytotoxicity pathways is controlled. Without perforin, NK cells were unable to perform GrzB-mediated serial killing and only killed once via death receptors. In contrast, the absence of CD95 on tumor targets did not impair GrzB-mediated serial killing. This demonstrates that GrzB and death receptor–mediated cytotoxicity are differentially regulated during NK cell serial killing.
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| 8. |
- Sieverling, Lina, et al.
(författare)
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Genomic footprints of activated telomere maintenance mechanisms in cancer
- 2020
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.
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| 9. |
- Zapatka, Marc, et al.
(författare)
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The landscape of viral associations in human cancers
- 2020
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 52:3, s. 320-330
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Tidskriftsartikel (refereegranskat)abstract
- Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, for which whole-genome and-for a subset-whole-transcriptome sequencing data from 2,658 cancers across 38 tumor types was aggregated, we systematically investigated potential viral pathogens using a consensus approach that integrated three independent pipelines. Viruses were detected in 382 genome and 68 transcriptome datasets. We found a high prevalence of known tumor-associated viruses such as Epstein-Barr virus (EBV), hepatitis B virus (HBV) and human papilloma virus (HPV; for example, HPV16 or HPV18). The study revealed significant exclusivity of HPV and driver mutations in head-and-neck cancer and the association of HPV with APOBEC mutational signatures, which suggests that impaired antiviral defense is a driving force in cervical, bladder and head-and-neck carcinoma. For HBV, HPV16, HPV18 and adeno-associated virus-2 (AAV2), viral integration was associated with local variations in genomic copy numbers. Integrations at the TERT promoter were associated with high telomerase expression evidently activating this tumor-driving process. High levels of endogenous retrovirus (ERV1) expression were linked to a worse survival outcome in patients with kidney cancer.
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