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- Waszak, S. M., et al.
(author)
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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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In: Lancet Oncology. - : Elsevier BV. - 1470-2045. ; 19:6, s. 785-798
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Journal article (peer-reviewed)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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| 2. |
- Waszak, S. M., et al.
(author)
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Germline Elongator mutations in Sonic Hedgehog medulloblastoma
- 2020
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 580:7803
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Journal article (peer-reviewed)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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| 5. |
- Fahmideh, M. A., et al.
(author)
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CCDC26, CDKN2BAS, RTEL1 and TERT Polymorphisms in pediatric brain tumor susceptibility
- 2015
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In: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 51, s. S163-S163
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Journal article (peer-reviewed)abstract
- The role of genetic polymorphisms in pediatric brain tumor (PBT) etiology is poorly understood. We hypothesized that single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) on adult glioma would also be associated with PBT risk. The study is based on the Cefalo study, a population-based multicenter case-control study. Saliva DNA from 245 cases and 489 controls, aged 7-19 years at diagnosis/reference date, was extracted and genotyped for 29 SNPs reported by GWAS to be significantly associated with risk of adult glioma. Data were analyzed using unconditional logistic regression. Stratified analyses were performed for two histological subtypes: astrocytoma alone and the other tumor types combined. The results indicated that four SNPs, CDKN2BAS rs4977756 (p = 0.036), rs1412829 (p = 0.037), rs2157719 (p = 0.018) and rs1063192 (p = 0.021), were associated with an increased susceptibility to PBTs, whereas the TERT rs2736100 was associated with a decreased risk (p = 0.018). Moreover, the stratified analyses showed a decreased risk of astrocytoma associated with RTEL1 rs6089953, rs6010620 and rs2297440 (p(trend) = 0.022, p(trend) = 0.042, p(trend) = 0.029, respectively) as well as an increased risk of this subtype associated with RTEL1 rs4809324 (p(trend) = 0.033). In addition, SNPs rs10464870 and rs891835 in CCDC26 were associated with an increased risk of non-astrocytoma tumor subtypes (p(trend) = 0.009, p(trend) = 0.007, respectively). Our findings indicate that SNPs in CDKN2BAS, TERT, RTEL1 and CCDC26 may be associated with the risk of PBTs. Therefore, we suggest that pediatric and adult brain tumors might share common genetic risk factors and similar etiological pathways.
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| 21. |
- Roosli, M, et al.
(author)
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Brain and Salivary Gland Tumors and Mobile Phone Use: Evaluating the Evidence from Various Epidemiological Study Designs
- 2019
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In: Annual review of public health. - : Annual Reviews. - 1545-2093 .- 0163-7525. ; 40, s. 221-238
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Journal article (peer-reviewed)abstract
- Mobile phones (MPs) are the most relevant source of radiofrequency electromagnetic field (RF-EMF) exposure to the brain and the salivary gland. Whether this exposure implies a cancer risk has been addressed in several case-control and few cohort studies. A meta-analysis of these studies does not show increased risks for meningioma, pituitary, and salivary gland tumors. For glioma and acoustic neuroma, the results are heterogeneous, with few case-control studies reporting substantially increased risks. However, these elevated risks are not coherent with observed incidence time trends, which are considered informative for this specific topic owing to the steep increase in MP use, the availability of virtually complete cancer registry data from many countries, and the limited number of known competing environmental risk factors. In conclusion, epidemiological studies do not suggest increased brain or salivary gland tumor risk with MP use, although some uncertainty remains regarding long latency periods (>15 years), rare brain tumor subtypes, and MP usage during childhood.
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| 22. |
- Dobrev, Ivo, et al.
(author)
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Sound wave propagation on the human skull surface with bone conduction stimulation
- 2017
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In: Hearing Research. - : ELSEVIER SCIENCE BV. - 0378-5955 .- 1878-5891. ; 355
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Journal article (peer-reviewed)abstract
- Background: Bone conduction (BC) is an alternative to air conduction to stimulate the inner ear. In general, the stimulation for BC occurs on a specific location directly on the skull bone or through the skin covering the skull bone. The stimulation propagates to the ipsilateral and contralateral cochlea, mainly via the skull bone and possibly via other skull contents. This study aims to investigate the wave propagation on the surface of the skull bone during BC stimulation at the forehead and at ipsilateral mastoid. Methods: Measurements were performed in five human cadaveric whole heads. The electro-magnetic transducer from a BCHA (bone conducting hearing aid), a Baha (R) Cordelle II transducer in particular, was attached to a percutaneously implanted screw or positioned with a 5-Newton steel headband at the mastoid and forehead. The Baha transducer was driven directly with single tone signals in the frequency range of 0.25-8 kHz, while skull bone vibrations were measured at multiple points on the skull using a scanning laser Doppler vibrometer (SLDV) system and a 3D LDV system. The 3D velocity components, defined by the 3D LDV measurement coordinate system, have been transformed into tangent (in-plane) and normal (out-of-plane) components in a local intrinsic coordinate system at each measurement point, which is based on the cadaver heads shape, estimated by the spatial locations of all measurement points. Results: Rigid-body-like motion was dominant at low frequencies below 1 kHz, and clear transverse traveling waves were observed at high frequencies above 2 kHz for both measurement systems. The surface waves propagation speeds were approximately 450 m/s at 8 kHz, corresponding trans-cranial time interval of 0.4 ms. The 3D velocity measurements confirmed the complex space and frequency dependent response of the cadaver heads indicated by the ID data from the SLDV system. Comparison between the tangent and normal motion components, extracted by transforming the 3D velocity components into a local coordinate system, indicates that the normal component, with spatially varying phase, is dominant above 2 kHz, consistent with local bending vibration modes and traveling surface waves. Conclusion: Both SLDV and 3D LDV data indicate that sound transmission in the skull bone causes rigid body-like motion at low frequencies whereas transverse deformations and travelling waves were observed above 2 kHz, with propagation speeds of approximately of 450 m/s at 8 kHz. (C) 2017 Elsevier B.V. All rights reserved.
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| 23. |
- Maier, Hannes, et al.
(author)
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Consensus Statement on Bone Conduction Devices and Active Middle Ear Implants in Conductive and Mixed Hearing Loss
- 2022
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In: Otology and Neurotology. - : Lippincott, Williams & Wilkins. - 1531-7129 .- 1537-4505. ; 43:5, s. 513-529
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Journal article (peer-reviewed)abstract
- Nowadays, several options are available to treat patients with conductive or mixed hearing loss. Whenever surgical intervention is not possible or contra-indicated, and amplification by a conventional hearing device (e.g., behind-the-ear device) is not feasible, then implantable hearing devices are an indispensable next option. Implantable bone-conduction devices and middle-ear implants have advantages but also limitations concerning complexity/invasiveness of the surgery, medical complications, and effectiveness. To counsel the patient, the clinician should have a good overview of the options with regard to safety and reliability as well as unequivocal technical performance data. The present consensus document is the outcome of an extensive iterative process including ENT specialists, audiologists, health-policy scientists, and representatives/technicians of the main companies in this field. This document should provide a first framework for procedures and technical characterization to enhance effective communication between these stakeholders, improving health care.
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| 24. |
- Roosli, Christof, et al.
(author)
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Intracranial Pressure and Promontory Vibration With Soft Tissue Stimulation in Cadaveric Human Whole Heads
- 2016
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In: Otology and Neurotology. - : LIPPINCOTT WILLIAMS & WILKINS. - 1531-7129 .- 1537-4505. ; 37:9, s. E384-E390
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Journal article (peer-reviewed)abstract
- Hypothesis:Intracranial pressure and skull vibrations are correlated and depend on the stimulation position and frequency.Background:A hearing sensation can be elicited by vibratory stimulation on the skin covered skull, or by stimulation on soft tissue such as the neck. It is not fully understood whether different stimulation sites induce the skull vibrations responsible for the perception or whether other transmission pathways are dominant. The aim of this study was to assess the correlation between intracranial pressure and skull vibration measured on the promontory for stimulation to different sites on the head.Methods:Measurements were performed on four human cadaver heads. A bone conduction hearing aid was held in place with a 5-Newton steel headband at four locations (mastoid, forehead, eye, and neck). While stimulating in the frequency range of 0.3 to 10kHz, acceleration of the cochlear promontory was measured with a Laser Doppler Vibrometer, and intracranial pressure at the center of the head with a hydrophone.Results:Promontory acceleration and intracranial pressure was measurable for all stimulation sites. The ratios were comparable between all stimulation sites for frequencies below 2kHz.Conclusion:These findings indicate that both promontory acceleration and intracranial pressure are involved for stimulation on the sites investigated. The transmission pathway of sound energy is comparable for the four stimulation sites.
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| 25. |
- Sim, J. H., et al.
(author)
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Interaction between osseous and non-osseous vibratory stimulation of the human cadaveric head
- 2016
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In: Hearing Research. - : ELSEVIER SCIENCE BV. - 0378-5955 .- 1878-5891. ; 340, s. 153-160
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Journal article (peer-reviewed)abstract
- Bone conduction (BC) stimulation can be applied by vibration to the bony or skin covered skull (osseous BC), or on soft tissue such as the neck (non-osseous BC). The interaction between osseous and non osseous bone conduction pathways is assessed in this study. The relation between bone vibrations measured at the cochlear promontory and the intracranial sound pressure for stimulation directly on the dura and for stimulation at the mastoid between 0.2 and 10 kHz was compared. First, for stimulation on the dura, varying the static coupling force of the BC transducer on the dura had only a small effect on promontory vibration. Second, the presence or absence of intracranial fluid did not affect promontory vibration for stimulation on the dura. Third, stimulation on the mastoid elicited both promontory vibration and intracranial sound pressure. Stimulation on the dura caused intracranial sound pressure to a similar extent above 0.5 kHz compared to stimulation on the mastoid, while promontory vibration was less by 20-40 dB. From these findings, we conclude that intracranial sound pressure (non-osseous BC) only marginally affects bone vibrations measured on the promontory (osseous BC), whereas skull vibrations affect intracranial sound pressure. (C) 2016 Elsevier B.V. All rights reserved.
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