| 1. |
- 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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| 2. |
- Cuppen, Edwin, et al.
(author)
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Implementation of Whole-Genome and Transcriptome Sequencing Into Clinical Cancer Care
- 2022
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In: JCO Precision Oncology. - : American Society of Clinical Oncology. - 2473-4284. ; 6
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Journal article (peer-reviewed)abstract
- PURPOSE The combination of whole-genome and transcriptome sequencing (WGTS) is expected to transformdiagnosis and treatment for patients with cancer. WGTS is a comprehensive precision diagnostic test that isstarting to replace the standard of care for oncology molecular testing in health care systems around the world;however, the implementation and widescale adoption of this best-in-class testing is lacking.METHODS Here, we address the barriers in integrating WGTS for cancer diagnostics and treatment selection andanswer questions regarding utility in different cancer types, cost-effectiveness and affordability, and otherpractical considerations for WGTS implementation.RESULTS We review the current studies implementing WGTS in health care systems and provide a synopsis of theclinical evidence and insights into practical considerations for WGTS implementation. We reflect on regulatory,costs, reimbursement, and incidental findings aspects of this test.CONCLUSION WGTS is an appropriate comprehensive clinical test for many tumor types and can replacemultiple, cascade testing approaches currently performed. Decreasing sequencing cost, increasing number ofclinically relevant aberrations and discovery of more complex biomarkers of treatment response, should pave theway for health care systems and laboratories in implementing WGTS into clinical practice, to transform diagnosisand treatment for patients with cancer.
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| 3. |
- Demichev, Vadim, et al.
(author)
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A time-resolved proteomic and prognostic map of COVID-19
- 2021
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In: Cell Systems. - : Elsevier BV. - 2405-4712 .- 2405-4720. ; 12:8, s. 780-794.e7
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Journal article (peer-reviewed)abstract
- COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease.
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| 4. |
- 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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| 5. |
- Messner, Christoph B., et al.
(author)
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Ultra-High-Throughput Clinical Proteomics Reveals Classifiers of COVID-19 Infection
- 2020
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In: Cell Systems. - : Elsevier BV. - 2405-4712 .- 2405-4720. ; 11:1, s. 11-24.E4
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Journal article (peer-reviewed)abstract
- The COVID-19 pandemic is an unprecedented global challenge, and point-of-care diagnostic classifiers are urgently required. Here, we present a platform for ultra-high-throughput serum and plasma proteomics that builds on ISO13485 standardization to facilitate simple implementation in regulated clinical laboratories. Our low-cost workflow handles up to 180 samples per day, enables high precision quantification, and reduces batch effects for large-scale and longitudinal studies. We use our platform on samples collected from a cohort of early hospitalized cases of the SARS-CoV-2 pandemic and identify 27 potential biomarkers that are differentially expressed depending on the WHO severity grade of COVID-19. They include complement factors, the coagulation system, inflammation modulators, and pro-inflammatory factors upstream and downstream of interleukin 6. All protocols and software for implementing our approach are freely available. In total, this work supports the development of routine proteomic assays to aid clinical decision making and generate hypotheses about potential COVID-19 therapeutic targets.
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| 6. |
- Scheer, Monika, et al.
(author)
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Desmoplastic small round cell tumors : Multimodality treatment and new risk factors
- 2019
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In: Cancer Medicine. - : WILEY. - 2045-7634. ; 8:2, s. 527-542
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Journal article (peer-reviewed)abstract
- Background: To evaluate optimal therapy and potential risk factors.Methods: Data of DSRCT patients <40 years treated in prospective CWS trials 1997‐2015 were analyzed.Results: Median age of 60 patients was 14.5 years. Male:female ratio was 4:1. Tumors were abdominal/retroperitoneal in 56/60 (93%). 6/60 (10%) presented with a localized mass, 16/60 (27%) regionally disseminated nodes, and 38/60 (63%) with extraperitoneal metastases. At diagnosis, 23/60 (38%) patients had effusions, 4/60 (7%) a thrombosis, and 37/54 (69%) elevated CRP. 40/60 (67%) patients underwent tumor resection, 21/60 (35%) macroscopically complete. 37/60 (62%) received chemotherapy according to CEVAIE (ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide), 15/60 (25%) VAIA (ifosfamide, vincristine, adriamycin, actinomycin D) and, 5/60 (8%) P6 (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide). Nine received high‐dose chemotherapy, 6 received regional hyperthermia, and 20 received radiotherapy. Among 25 patients achieving complete remission, 18 (72%) received metronomic therapies. Three‐year event‐free (EFS) and overall survival (OS) were 11% (±8 confidence interval [CI] 95%) and 30% (±12 CI 95%), respectively, for all patients and 26.7% (±18.0 CI 95%) and 56.9% (±20.4 CI 95%) for 25 patients achieving remission. Extra‐abdominal site, localized disease, no effusion or ascites only, absence of thrombosis, normal CRP, complete tumor resection, and chemotherapy with VAIA correlated with EFS in univariate analysis. In multivariate analysis, significant factors were no thrombosis and chemotherapy with VAIA. In patients achieving complete remission, metronomic therapy with cyclophosphamide/vinblastine correlated with prolonged time to relapse.Conclusion: Pleural effusions, venous thrombosis, and CRP elevation were identified as potential risk factors. The VAIA scheme showed best outcome. Maintenance therapy should be investigated further.
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