| 1. |
- Hudson, Thomas J., et al.
(author)
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International network of cancer genome projects
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
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Journal article (peer-reviewed)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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| 2. |
- Northcott, Paul A, et al.
(author)
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Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma.
- 2014
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 511:7510, s. 428-428
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Journal article (peer-reviewed)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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| 3. |
- Alexandrov, Ludmil B., et al.
(author)
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Signatures of mutational processes in human cancer
- 2013
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 500:7463, s. 415-421
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Journal article (peer-reviewed)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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| 4. |
- Barbus, Sebastian, et al.
(author)
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Differential retinoic acid signaling in tumors of long- and short-term glioblastoma survivors.
- 2011
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 103:7
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Journal article (peer-reviewed)abstract
- Although the prognosis of most glioblastoma patients is poor, 3%-5% patients show long-term survival of 36 months or longer after diagnosis. To study the differences in activation of biochemical pathways, we performed mRNA and protein expression analyses of primary glioblastoma tissues from 11 long-term survivors (LTS; overall survival ≥ 36 months) and 12 short-term survivors (STS; overall survival ≤ 6 months). The mRNA expression ratio of the retinoic acid transporters fatty acid-binding protein 5 (FABP5) and cellular retinoic acid-binding protein 2 (CRABP2), which regulate the differential delivery of retinoic acid to either antioncogenic retinoic acid receptors or prooncogenic nuclear receptor peroxisome proliferator-activated receptor delta, was statistically significantly higher in the tumor tissues of STS than those of LTS (median ratio in STS tumors = 3.64, 10th-90th percentile = 1.43-4.54 vs median ratio in LTS tumors = 1.42, 10th-90th percentile = -0.98 to 2.59; P < .001). High FABP5 protein expression in STS tumors was associated with highly proliferating tumor cells and activation of 3-phosphoinositide-dependent protein kinase-1 and v-akt murine thymoma viral oncogene homolog. The data suggest that retinoic acid signaling activates different targets in glioblastomas from LTS and STS. All statistical tests were two-sided.
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| 5. |
- Haag, Daniel, et al.
(author)
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Nos2 inactivation promotes the development of medulloblastoma in Ptch1(+/-) mice by deregulation of Gap43-dependent granule cell precursor migration.
- 2012
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In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3
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Journal article (peer-reviewed)abstract
- Medulloblastoma is the most common malignant brain tumor in children. A subset of medulloblastoma originates from granule cell precursors (GCPs) of the developing cerebellum and demonstrates aberrant hedgehog signaling, typically due to inactivating mutations in the receptor PTCH1, a pathomechanism recapitulated in Ptch1(+/-) mice. As nitric oxide may regulate GCP proliferation and differentiation, we crossed Ptch1(+/-) mice with mice lacking inducible nitric oxide synthase (Nos2) to investigate a possible influence on tumorigenesis. We observed a two-fold higher medulloblastoma rate in Ptch1(+/-) Nos2(-/-) mice compared to Ptch1(+/-) Nos2(+/+) mice. To identify the molecular mechanisms underlying this finding, we performed gene expression profiling of medulloblastomas from both genotypes, as well as normal cerebellar tissue samples of different developmental stages and genotypes. Downregulation of hedgehog target genes was observed in postnatal cerebellum from Ptch1(+/+) Nos2(-/-) mice but not from Ptch1(+/-) Nos2(-/-) mice. The most consistent effect of Nos2 deficiency was downregulation of growth-associated protein 43 (Gap43). Functional studies in neuronal progenitor cells demonstrated nitric oxide dependence of Gap43 expression and impaired migration upon Gap43 knock-down. Both effects were confirmed in situ by immunofluorescence analyses on tissue sections of the developing cerebellum. Finally, the number of proliferating GCPs at the cerebellar periphery was decreased in Ptch1(+/+) Nos2(-/-) mice but increased in Ptch1(+/-) Nos2(-/) (-) mice relative to Ptch1(+/-) Nos2(+/+) mice. Taken together, these results indicate that Nos2 deficiency promotes medulloblastoma development in Ptch1(+/-) mice through retention of proliferating GCPs in the external granular layer due to reduced Gap43 expression. This study illustrates a new role of nitric oxide signaling in cerebellar development and demonstrates that the localization of pre-neoplastic cells during morphogenesis is crucial for their malignant progression.
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| 6. |
- Kokocinski, Felix, et al.
(author)
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FACT--a framework for the functional interpretation of high-throughput experiments.
- 2005
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In: BMC Bioinformatics. - : Springer Science and Business Media LLC. - 1471-2105. ; 6
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Journal article (peer-reviewed)abstract
- BACKGROUND: Interpreting the results of high-throughput experiments, such as those obtained from DNA-microarrays, is an often time-consuming task due to the high number of data-points that need to be analyzed in parallel. It is usually a matter of extensive testing and unknown beforehand, which of the possible approaches for the functional analysis will be the most informative.RESULTS: To address this problem, we have developed the Flexible Annotation and Correlation Tool (FACT). FACT allows for detection of important patterns in large data sets by simplifying the integration of heterogeneous data sources and the subsequent application of different algorithms for statistical evaluation or visualization of the annotated data. The system is constantly extended to include additional annotation data and comparison methods.CONCLUSION: FACT serves as a highly flexible framework for the explorative analysis of large genomic and proteomic result sets. The program can be used online; open source code and supplementary information are available at http://www.factweb.de.
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| 7. |
- Lehmann, Barry-Detlef, et al.
(author)
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Towards the Identification of Process Anti-Patterns in Enterprise Architecture Models
- 2020
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In: 8th International Workshop on Quantitative Approaches to Software Quality (QuASoQ 2020). - : CEUR-WS.org. ; , s. 47-54
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Conference paper (peer-reviewed)abstract
- IT processes constitute the backbone of an integrated enterprise architecture (EA). The model thereof sustains the development and management of the EA. Nevertheless, the quality of such models tends to degrade over time due to, e.g. impropermodeling practices or ineffective evaluation. In this regard, the knowledge of relevant modeling anti-patterns can help identify, mitigate, and prevent the occurrence of sub-optimal or adverse constructs in the model. In the field of business processmodeling (BPM), a plethora of BPM anti-patterns has been defined and compiled in various taxonomies. However, these BPManti-patterns mostly focus on technical issues, which thus are applicable for evaluating workflows but not EA-level processes.We strongly argue that the concept of process anti-pattern in EA domain can facilitate EA analyses on process-related issues.To address this gap, this paper presents a catalogue of 18 EA process modeling anti-patterns, which we derived from theexisting BPM anti-patterns. Our result should serve as food for thought and motivation for future research in this context.
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| 8. |
- Mantripragada, Kiran K., 1975-
(author)
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Microarray-Based Comparative Genomic Hybridization in Neurofibromatoses and DiGeorge Syndrome
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Microarray-based comparative genomic hybridization (array-CGH) has emerged as a versatile platform with a wide range of applications in molecular genetics. This thesis focuses on the development of array-CGH with a specific aim to approach disease-related questions through improved strategies in array construction and enhanced resolution of analysis. In paper I, we applied an array covering 11 Mb of 22q, encompassing the NF2 locus, for deletion detection in sporadic schwannoma. Hemizygous deletions and tumor heterogeneity were identified. Array-CGH was established as a reliable platform for detection of DNA dosage alterations. Paper II described the construction of the NF2 gene-specific microarray for high-resolution scanning of deletions in the NF2 locus. We report a novel PCR-based non-redundant strategy for microarray fabrication, which considerably improved the sensitivity and reliability of deletion detection. Paper III reported the first tiling-path array comprehensively covering a human chromosome. The usefulness of the 22q-array was demonstrated by applying it to detect DNA dosage-alterations in 22q-associated disorders. In paper IV, we optimized array-CGH protocols for deletion detection in 22q11 deletion-syndrome. We showed that genomic and cDNA clones are not optimal for analysis of 22q11 locus and that PCR-based non-redundant strategy is reliable for deletion detection in such regions. In paper V, we utilized the 22q-array for understanding the genetic basis of schwannomatosis. Two commonly deleted regions were identified within the IGL and the GSTT1/CABIN1 loci. Further investigations using high-resolution arrays, bioinformatic analysis and mutational screening were performed. Missense mutations, specific to the schwannomatosis- and NF2 samples, were identified in the CABIN1 gene. Paper VI described the first array-CGH study for comprehensive and high-resolution profiling of deletions spanning the 17q11 locus. Both typical and atypical deletions were identified in NF1 samples. Bioinformatic analysis revealed novel segmental duplications, which can potentially mediate 17q11 deletions.
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| 9. |
- Peter, Alexander, et al.
(author)
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A Framework for Managing Enterprise Architecture Debts : Outline and Research Directions
- 2020
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Conference paper (peer-reviewed)abstract
- Even though enterprise architecture management (EAM) offers a wide range of methods and tools for aligning business with IT, an architect’s work is challenged by reality. The evolution of enterprise architecture (EA) and given constraints (e.g. legacy systems and processes) lead to debts which may complicate and hinder opportunities; however, the management of such debts has not been considered in EAM research. This paper presents a framework for strategically managing EA-debt-related issues and propose open questions as well as future research directions in this field.
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| 10. |
- Peter, N., et al.
(author)
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Common fragrance chemicals activate dendritic cells in coculture with keratinocytes
- 2023
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In: Contact Dermatitis. - 0105-1873. ; 89:1, s. 1-15
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Journal article (peer-reviewed)abstract
- Background: Fragrances are important contact allergens; however, investigation of their skin sensitization potency has been challenging in new approach methods (NAMs). Many fragrance chemicals are susceptible to autoxidation or can be metabolized by enzymes constitutively expressed in skin keratinocytes. Strong sensitizers can be formed in both of these processes. Further, keratinocytes can modulate the dendritic cell (DC) activation and maturation potential, a key event in the acquisition of contact allergy. Objectives: To evaluate the 2D coculture model consisting of keratinocytes and DCs using different weak to moderate sensitizing fragrance chemicals. Further, to investigate fragrances and related oxidation products in the in vitro model and compare to in vivo data. Methods: Chemicals were tested in the coculture activation test (COCAT), consisting of HaCaT keratinocytes and THP-1 cells. THP-1 cell surface expression of costimulatory and adhesion molecules (CD86 and CD54) collected after 24 h incubation with the chemicals was analysed using flow cytometry. Results: Twenty-four molecules were tested positive, three were negative (n = 27). Four pairs were evaluated, with aldehydes showing a 6- to 13-fold stronger responses compared to their corresponding alcohols. Conclusions: Results provide insight into the activation of DC in their natural environment of keratinocytes. alpha,beta-Unsaturated alcohols were classified as weaker sensitizers compared to their corresponding aldehydes. In sum, testing of fragrances retrieved results in good agreement with in vivo data.
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| 11. |
- Zapatka, Marc, et al.
(author)
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The landscape of viral associations in human cancers
- 2020
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 52:3, s. 320-330
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Journal article (peer-reviewed)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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