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- 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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- de van der Schueren, M. A. E., et al.
(författare)
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Global Leadership Initiative on Malnutrition (GLIM) : Guidance on validation of the operational criteria for the diagnosis of protein-energy malnutrition in adults
- 2020
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Ingår i: Clinical Nutrition. - : CHURCHILL LIVINGSTONE. - 0261-5614 .- 1532-1983. ; 39:9, s. 2872-2880
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Tidskriftsartikel (refereegranskat)abstract
- Background: The Global Leadership Initiative on Malnutrition (GLIM) created a consensus-based framework consisting of phenotypic and etiologic criteria to record the occurrence of malnutrition in adults. This is a minimum set of practicable indicators for use in characterizing a patient/client as malnourished, considering the global variations in screening and nutrition assessment, and to be used across different health care settings. As with other consensus-based frameworks for diagnosing disease states, these operational criteria require validation and reliability testing as they are currently based solely on expert opinion.Methods: Several forms of validation and reliability are reviewed in the context of GLIM, providing guidance on how to conduct retrospective and prospective studies for criterion and construct validity.Findings: There are some aspects of GLIM criteria which require refinement; research using large data bases can be employed to reach this goal. Machine learning is also introduced as a potential method to support identification of the best cut-points and combinations of operational criteria for use with the different forms of malnutrition, which the GLIM criteria were created to denote. It is noted as well that the validation and reliability testing need to occur in a variety of sectors, populations and with diverse persons completing the criteria.Conclusion: The guidance presented supports the conduct and publication of quality validation and reliability studies for GLIM.
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