| 1. |
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| 2. |
- Sliz, E., et al.
(författare)
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Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata
- 2023
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
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| 3. |
- Adcox, K, et al.
(författare)
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PHENIX detector overview
- 2003
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Ingår i: Nuclear Instruments & Methods in Physics Research. Section A: Accelerators, Spectrometers, Detectors, and Associated Equipment. - 0167-5087. ; 499:2-3, s. 469-479
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Tidskriftsartikel (refereegranskat)abstract
- The PHENIX detector is designed to perform a broad study of A-A, p-A, and p-p collisions to investigate nuclear matter under extreme conditions. A wide variety of probes, sensitive to all timescales, are used to study systematic variations with species and energy as well as to measure the spin structure of the nucleon. Designing for the needs of the heavy-ion and polarized-proton programs has produced a detector with unparalleled capabilities. PHENIX measures electron and muon pairs, photons, and hadrons with excellent energy and momentum resolution. The detector consists of a large number of subsystems that are discussed in other papers in this volume. The overall design parameters of the detector are presented. (C) 2002 Elsevier Science B.V. All rights reserved.
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| 4. |
- Rajewsky, N., et al.
(författare)
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LifeTime and improving European healthcare through cell-based interceptive medicine
- 2020
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Ingår i: Nature. - : Springer Nature. - 0028-0836 .- 1476-4687. ; 587:7834, s. 377-386
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Tidskriftsartikel (refereegranskat)abstract
- LifeTime aims to track, understand and target human cells during the onset and progression of complex diseases and their response to therapy at single-cell resolution. This mission will be implemented through the development and integration of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during progression from health to disease. Analysis of such large molecular and clinical datasets will discover molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. Timely detection and interception of disease embedded in an ethical and patient-centered vision will be achieved through interactions across academia, hospitals, patient-associations, health data management systems and industry. Applying this strategy to key medical challenges in cancer, neurological, infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.
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| 5. |
- Tabassum, R, et al.
(författare)
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Genetic architecture of human plasma lipidome and its link to cardiovascular disease
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 4329-
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Tidskriftsartikel (refereegranskat)abstract
- Understanding genetic architecture of plasma lipidome could provide better insights into lipid metabolism and its link to cardiovascular diseases (CVDs). Here, we perform genome-wide association analyses of 141 lipid species (n = 2,181 individuals), followed by phenome-wide scans with 25 CVD related phenotypes (n = 511,700 individuals). We identify 35 lipid-species-associated loci (P <5 ×10−8), 10 of which associate with CVD risk including five new loci-COL5A1, GLTPD2, SPTLC3, MBOAT7 and GALNT16 (false discovery rate<0.05). We identify loci for lipid species that are shown to predict CVD e.g., SPTLC3 for CER(d18:1/24:1). We show that lipoprotein lipase (LPL) may more efficiently hydrolyze medium length triacylglycerides (TAGs) than others. Polyunsaturated lipids have highest heritability and genetic correlations, suggesting considerable genetic regulation at fatty acids levels. We find low genetic correlations between traditional lipids and lipid species. Our results show that lipidomic profiles capture information beyond traditional lipids and identify genetic variants modifying lipid levels and risk of CVD.
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| 6. |
- Das, A., et al.
(författare)
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Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency
- 2022
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28:1, s. 125-135
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Tidskriftsartikel (refereegranskat)abstract
- Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy. © 2022, The Author(s).
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| 7. |
- Lee, James J, et al.
(författare)
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Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.
- 2018
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Ingår i: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 50:8, s. 1112-1121
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Tidskriftsartikel (refereegranskat)abstract
- Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1million individuals and identify 1,271independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11-13% of the variance in educational attainment and 7-10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.
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| 8. |
- Waszak, S. M., et al.
(författare)
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Germline Elongator mutations in Sonic Hedgehog medulloblastoma
- 2020
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 580:7803
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Tidskriftsartikel (refereegranskat)abstract
- Cancer genomics has revealed many genes and core molecular processes that contribute to human malignancies, but the genetic and molecular bases of many rare cancers remains unclear. Genetic predisposition accounts for 5 to 10% of cancer diagnoses in children(1,2), and genetic events that cooperate with known somatic driver events are poorly understood. Pathogenic germline variants in established cancer predisposition genes have been recently identified in 5% of patients with the malignant brain tumour medulloblastoma(3). Here, by analysing all protein-coding genes, we identify and replicate rare germline loss-of-function variants across ELP1 in 14% of paediatric patients with the medulloblastoma subgroup Sonic Hedgehog (MBSHH). ELP1 was the most common medulloblastoma predisposition gene and increased the prevalence of genetic predisposition to 40% among paediatric patients with MBSHH. Parent-offspring and pedigree analyses identified two families with a history of paediatric medulloblastoma. ELP1-associated medulloblastomas were restricted to the molecular SHH alpha subtype(4) and characterized by universal biallelic inactivation of ELP1 owing to somatic loss of chromosome arm 9q. Most ELP1-associated medulloblastomas also exhibited somatic alterations in PTCH1, which suggests that germline ELP1 loss-of-function variants predispose individuals to tumour development in combination with constitutive activation of SHH signalling. ELP1 is the largest subunit of the evolutionarily conserved Elongator complex, which catalyses translational elongation through tRNA modifications at the wobble (U-34) position(5,6). Tumours from patients with ELP1-associated MBSHH were characterized by a destabilized Elongator complex, loss of Elongator-dependent tRNA modifications, codon-dependent translational reprogramming, and induction of the unfolded protein response, consistent with loss of protein homeostasis due to Elongator deficiency in model systems(7-9). Thus, genetic predisposition to proteome instability may be a determinant in the pathogenesis of paediatric brain cancers. These results support investigation of the role of protein homeostasis in other cancer types and potential for therapeutic interference.
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| 9. |
- Agrell, Erik, 1965, et al.
(författare)
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Roadmap of optical communications
- 2016
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Ingår i: Journal of Optics. - : IOP Publishing. - 2040-8978 .- 2040-8986. ; 18:6
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Tidskriftsartikel (refereegranskat)abstract
- Lightwave communications is a necessity for the information age. Optical links provide enormous bandwidth, and the optical fiber is the only medium that can meet the modern society's needs for transporting massive amounts of data over long distances. Applications range from global high-capacity networks, which constitute the backbone of the internet, to the massively parallel interconnects that provide data connectivity inside datacenters and supercomputers. Optical communications is a diverse and rapidly changing field, where experts in photonics, communications, electronics, and signal processing work side by side to meet the ever-increasing demands for higher capacity, lower cost, and lower energy consumption, while adapting the system design to novel services and technologies. Due to the interdisciplinary nature of this rich research field, Journal of Optics has invited 16 researchers, each a world-leading expert in their respective subfields, to contribute a section to this invited review article, summarizing their views on state-of-the-art and future developments in optical communications.
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| 10. |
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| 11. |
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| 12. |
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| 13. |
- Bowers, Robert M., et al.
(författare)
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Minimum information about a single amplified genome (MISAG) and a metagenome-assembled genome (MIMAG) of bacteria and archaea
- 2017
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Ingår i: Nature Biotechnology. - : NATURE PUBLISHING GROUP. - 1087-0156 .- 1546-1696. ; 35:8, s. 725-731
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Tidskriftsartikel (refereegranskat)abstract
- We present two standards developed by the Genomic Standards Consortium (GSC) for reporting bacterial and archaeal genome sequences. Both are extensions of the Minimum Information about Any (x) Sequence (MIxS). The standards are the Minimum Information about a Single Amplified Genome (MISAG) and the Minimum Information about a Metagenome-Assembled Genome (MIMAG), including, but not limited to, assembly quality, and estimates of genome completeness and contamination. These standards can be used in combination with other GSC checklists, including the Minimum Information about a Genome Sequence (MIGS), Minimum Information about a Metagenomic Sequence (MIMS), and Minimum Information about a Marker Gene Sequence (MIMARKS). Community-wide adoption of MISAG and MIMAG will facilitate more robust comparative genomic analyses of bacterial and archaeal diversity.
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| 14. |
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| 15. |
- Corazzini, Kirsten N., et al.
(författare)
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Toward Common Data Elements for International Research in Long-term Care Homes : Advancing Person-Centered Care
- 2019
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Ingår i: Journal of the American Medical Directors Association. - : Elsevier. - 1525-8610 .- 1538-9375. ; 20:5, s. 598-603
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Tidskriftsartikel (refereegranskat)abstract
- To support person-centered, residential long-term care internationally, a consortium of researchers in medicine, nursing, behavioral, and social sciences from 21 geographically and economically diverse countries have launched the WE-THRIVE consortium to develop a common data infrastructure. WE-THRIVE aims to identify measurement domains that are internationally relevant, including in low-, middle-, and high-income countries, prioritize concepts to operationalize domains, and specify a set of data elements to measure concepts that can be used across studies for data sharing and comparisons. This article reports findings from consortium meetings at the 2016 meeting of the Gerontological Society of America and the 2017 meeting of the International Association of Gerontology and Geriatrics, to identify domains and prioritize concepts, following best practices to identify common data elements (CDEs) that were developed through the US National Institutes of Health/National Institute of Nursing Research's CDEs initiative. Four domains were identified, including organizational context, workforce and staffing, person-centered care, and care outcomes. Using a nominal group process, WE-THRIVE prioritized 21 concepts across the 4 domains. Several concepts showed similarity to existing measurement structures, whereas others differed. Conceptual similarity (convergence; eg, concepts in the care outcomes domain of functional level and harm-free care) provides further support of the critical foundational work in LTC measurement endorsed and implemented by regulatory bodies. Different concepts (divergence; eg, concepts in the person-centered care domain of knowing the person and what matters most to the person) highlights current gaps in measurement efforts and is consistent with WE-THRIVE's focus on supporting resilience and thriving for residents, family, and staff. In alignment with the World Health Organization's call for comparative measurement work for health systems change, WE-THRIVE's work to date highlights the benefits of engaging with diverse LTC researchers, including those in low-, middle-, and high-income countries, to develop a measurement infrastructure that integrates the aspirations of person-centered LTC.
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| 16. |
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| 17. |
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| 18. |
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| 19. |
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| 20. |
- Gaver, W. W., et al.
(författare)
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The Drift Table : Designing for ludic engagement
- 2004
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Ingår i: Conf Hum Fact Comput Syst Proc. - New York, NY, USA : ACM. - 1581137036 - 9781581137033 ; , s. 885-900
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Konferensbidrag (refereegranskat)abstract
- The Drift Table is an electronic coffee table that displays slowly moving aerial photography controlled by the distribution of weight on its surface. It was designed to investigate our ideas about how technologies for the home could support ludic activities-that is, activities motivated by curiosity, exploration, and reflection rather than externally-defined tasks. The many design choices we made, for example to block or disguise utilitarian functionality, helped to articulate our emerging understanding of ludic design. Observations of the Drift Table being used in volunteers' homes over several weeks gave greater insight into how playful exploration is practically achieved and the issues involved in designing for ludic engagement.
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| 21. |
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| 22. |
- Marao, Heloisa F., et al.
(författare)
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Cortical and Trabecular Bone Healing Patterns and Quantification for Three Different Dental Implant Systems
- 2017
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Ingår i: International Journal of Oral & Maxillofacial Implants. - : Quintessence. - 0882-2786 .- 1942-4434. ; 32:3, s. 585-592
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The present study hypothesized that different bone healing patterns through initial stages of osseointegration would be observed when three distinct commercially available implant systems (Nobel Groovy, Implacil, and Zimmer TSV) were used, leading to significant variations in histometric levels of total bone and new bone formation during the osseointegration process. Materials and Methods: A total of 48 implants were placed bilaterally on the tibias of eight beagle dogs and allowed to heal for 2 and 6 weeks. Following euthanasia, nondecalcified specimens were processed for morphologic and histometric evaluation. Bone-to-implant contact (BIC) and new bone area fraction occupancy (BAFO) analyses for native and new bone were performed along the whole perimeter of each implant and separately for the cortical and trabecular bone regions. Results: Morphologic evaluation of cortical bone presented different healing patterns and osseointegration levels for different implant systems as time elapsed in vivo. Interfacial remodeling was the chief healing pattern in Zimmer implants, while a combination of interfacial remodeling and healing chambers was observed in Nobel and Implacil implants. When trabecular bone was evaluated, similar bone healing patterns were observed between systems despite different levels of osseointegration observed as a function of implantation time, implant system, and native and/or new bone BIC and BAFO. Conclusion: Different implant systems led to different healing patterns during early stages of osseointegration. Such variation in pattern was more noticeable in the cortical regions compared to the trabecular regions. The variation in bone healing pattern did significantly influence overall indicators of native and new BIC and BAFO during the osseointegration process. The postulated hypothesis was accepted.
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| 23. |
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| 24. |
- Park, Hyundai, et al.
(författare)
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Device and Integration Technology for Silicon Photonic Transmitters
- 2011
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Ingår i: IEEE Journal of Selected Topics in Quantum Electronics. - 1077-260X .- 1558-4542. ; 17:3, s. 671-688
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Tidskriftsartikel (refereegranskat)abstract
- The device and integration technology for silicon photonic transmitters are reviewed in this paper. The hybrid silicon platform enables on-chip lasers to be fabricated with silicon photonic circuits and can be integrated in the CMOS back-end flow. Laser arrays from multiple die bonding and quantum well intermixing techniques are demonstrated to extend the spectral bandwidth from the laser array of the transmitter. Two modulator technologies, silicon modulators and hybrid silicon modulators, are also described.
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| 25. |
- Raj, Rajendra, et al.
(författare)
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Professional Competencies in Computing Education : Pedagogies and Assessment
- 2021
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Ingår i: ITiCSE-WGR '21: Proceedings of the 2021 Working Group Reports on Innovation and Technology in Computer Science Education. - New York, USA : Association for Computing Machinery (ACM). - 9781450392020 ; , s. 133-161
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Konferensbidrag (refereegranskat)abstract
- Competency-based learning has been a successful pedagogical approach for centuries, but only recently has it gained traction within computing. Competencies, as defined in Computing Curricula 2020, comprise knowledge, skills, and professional dispositions. Building on recent developments in competency and computing education, this working group examined relevant pedagogical theories, investigates various skill frameworks, reviewed competencies and standard practices in other professional disciplines such as medicine and law. It also investigated the integrative nature of content knowledge, skills, and professional dispositions in defining professional competencies in computing education. In addition, the group explored appropriate pedagogies and competency assessment approaches. It also developed guidelines for evaluating student achievement against relevant professional competency frameworks and explores partnering with employers to offer students genuine professional experience. Finally, possible challenges and opportunities in moving from traditional knowledge-based to competency-based education were also examined. This report makes recommendations to inspire educators of future computing professionals and smooth students' transition from academia to employment.
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| 26. |
- Raj, Rajendra, et al.
(författare)
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Toward Practical Computing Competencies
- 2021
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Ingår i: ITiCSE '21: Proceedings of the 26th ACM Conference on Innovation and Technology in Computer Science Education. - New York, NY, USA : ACM. ; , s. 603-604
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Konferensbidrag (refereegranskat)abstract
- Competency-based learning has been a successful pedagogical approach for centuries, but only recently has it gained traction within computing education. Building on recent developments in the field, this working group will explore competency-based learning from practical considerations and show how it benefits computing. In particular, the group will identify existing computing competencies and provide a pathway to generate competencies usable in the field. The working group will also investigate appropriate assessment approaches, provide guidelines for evaluating student attainment, and show how accrediting agencies can use these techniques to assess the level of competence reflected in their standards and criteria. Recommendations from the working group report are intended to help practical computing education writ large.
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| 27. |
- Sun, Yanting, et al.
(författare)
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Optical and structural properties of sulfur-doped ELOG InP on Si
- 2015
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Ingår i: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 117:21
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Tidskriftsartikel (refereegranskat)abstract
- Optical and structural properties of sulfur-doped epitaxial lateral overgrowth (ELOG) InP grown from nano-sized openings on Si are studied by room-temperature cathodoluminescence and cross-sectional transmission electron microscopy (XTEM). The dependence of luminescence intensity on opening orientation and dimension is reported. Impurity enhanced luminescence can be affected by the facet planes bounding the ELOG layer. Dark line defects formed along the [011] direction are identified as the facet planes intersected by the stacking faults in the ELOG layer. XTEM imaging in different diffraction conditions reveals that stacking faults in the seed InP layer can circumvent the SiO2 mask during ELOG and extend to the laterally grown layer over the mask. A model for Suzuki effect enhanced stacking fault propagation over the mask in sulfur-doped ELOG InP is constructed and in-situ thermal annealing process is proposed to eliminate the seeding stacking faults.
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| 28. |
- Svoboda, B. E., et al.
(författare)
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THE BOLOCAM GALACTIC PLANE SURVEY. XIV. PHYSICAL PROPERTIES of MASSIVE STARLESS and STAR-FORMING CLUMPS
- 2016
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 822:2
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Tidskriftsartikel (refereegranskat)abstract
- We sort 4683 molecular clouds between 10° < ℓ < 65° from the Bolocam Galactic Plane Survey based on observational diagnostics of star formation activity: compact 70 μm sources, mid-IR color-selected YSOs, H2O and CH3OH masers, and UCH ii regions. We also present a combined NH3-derived gas kinetic temperature and H2O maser catalog for 1788 clumps from our own GBT 100 m observations and from the literature. We identify a subsample of 2223 (47.5%) starless clump candidates (SCCs), the largest and most robust sample identified from a blind survey to date. Distributions of flux density, flux concentration, solid angle, kinetic temperature, column density, radius, and mass show strong (>1 dex) progressions when sorted by star formation indicator. The median SCC is marginally subvirial (α ∼ 0.7) with >75% of clumps with known distance being gravitationally bound (α < 2). These samples show a statistically significant increase in the median clump mass of ΔM ∼ 170-370 M o from the starless candidates to clumps associated with protostars. This trend could be due to (i) mass growth of the clumps at M o Myr-1 for an average freefall 0.8 Myr timescale, (ii) a systematic factor of two increase in dust opacity from starless to protostellar phases, and/or (iii) a variation in the ratio of starless to protostellar clump lifetime that scales as ∼M -0.4. By comparing to the observed number of CH3OH maser containing clumps, we estimate the phase lifetime of massive (M > 103 M o) starless clumps to be 0.37 ± 0.08 Myr (M/103 M o)-1; the majority (M < 450 M o) have phase lifetimes longer than their average freefall time. © 2016. The American Astronomical Society. All rights reserved.
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| 29. |
- Waszak, S. M., et al.
(författare)
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Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort
- 2018
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Ingår i: Lancet Oncology. - : Elsevier BV. - 1470-2045. ; 19:6, s. 785-798
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Tidskriftsartikel (refereegranskat)abstract
- Background Medulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines. Methods In this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma. Findings We included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 4069) and 5-year overall survival was 65% (95% CI 5281); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes. Interpretation Genetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics. Copyright (c) 2018 The Author(s). Published by Elsevier Ltd.
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